rs149399707

chr2-215052509-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_173076.3(ABCA12):c.485C>T(p.Ala162Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,612,514 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A162P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (7 hom.)
• Consequence: ABCA12 NM_173076.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 1.32

Genes affected

ABCA12 (HGNC:14637): (ATP binding cassette subfamily A member 12) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, and White). This encoded protein is a member of the ABC1 subfamily, which is the only major ABC subfamily found exclusively in multicellular eukaryotes. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013969272).
• BP6: Variant 2-215052509-G-A is Benign according to our data. Variant chr2-215052509-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235587.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=3, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00124 (189/152140) while in subpopulation NFE AF= 0.00219 (149/67978). AF 95% confidence interval is 0.0019. There are 0 homozygotes in gnomad4. There are 77 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA12	NM_173076.3	c.485C>T	p.Ala162Val	missense_variant	5/53	ENST00000272895.12
ABCA12	XM_011510951.3	c.485C>T	p.Ala162Val	missense_variant	5/53
ABCA12	NR_103740.2	n.903C>T		non_coding_transcript_exon_variant	5/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA12	ENST00000272895.12	c.485C>T	p.Ala162Val	missense_variant	5/53	1	NM_173076.3	P1
	ENST00000628464.2	n.1021+7992G>A		intron_variant, non_coding_transcript_variant		5
	ENST00000626134.2	n.404+7992G>A		intron_variant, non_coding_transcript_variant		5
	ENST00000626771.1	n.338+7992G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 152022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.00139 AC: 349 AN: 250822 Hom.: 2 AF XY: 0.00151 AC XY: 204 AN XY: 135536

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00222

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00156 AC: 2274 AN: 1460374 Hom.: 7 Cov.: 31 AF XY: 0.00156 AC XY: 1132 AN XY: 726510

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00157

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.00177

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00124 AC: 189 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.00104 AC XY: 77 AN XY: 74388

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00219

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.00185 Hom.: 2

Bravo AF: 0.00140

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00140 AC: 170

EpiCase AF: 0.00196

EpiControl AF: 0.00267

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	ABCA12: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2017	The A162V variant in the ABCA12 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, it is reported as a variant of uncertain significance in ClinVar by two different clinical laboratories, but additional evidence is not available (ClinVar SCV000281280.1 and SCV000427323.2; Landrum et al., 2016). The A162V variant is observed in 124/66,462 alleles (0.19%) from individuals of non-Finnish European background in the ExAC dataset, including one homozygous control individual (Lek et al., 2016). The A162V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In addition, this substitution occurs at a position that is not conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret A162V as a variant of uncertain significance. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Congenital ichthyosis of skin Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 03, 2022

Variant summary: ABCA12 c.485C>T (p.Ala162Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 250822 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 2.1 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCA12 causing Lamellar Ichthyosis phenotype (0.00066), strongly suggesting that the variant is benign. To our knowledge, no penetrant association c.485C>T in individuals affected with Lamellar Ichthyosis and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as benign. -

ABCA12-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.15
Sift	Benign	0.16	T
Sift4G	Benign	0.093	T
Polyphen		0.047	B
Vest4		0.39
MVP		0.69
MPC		0.19
ClinPred		0.011	T
GERP RS		3.7
Varity_R		0.064
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs149399707; hg19: chr2-215917233;