rs148979792

Positions:

• chr2-215018025-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173076.3(ABCA12):​c.1765C>A​(p.Pro589Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00905 in 1,614,056 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0093 (84 hom.)
• Consequence: ABCA12 NM_173076.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.56

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006954968).
• BP6: Variant 2-215018025-G-T is Benign according to our data. Variant chr2-215018025-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 262821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00692 (1054/152260) while in subpopulation AMR AF= 0.0127 (194/15294). AF 95% confidence interval is 0.0112. There are 6 homozygotes in gnomad4. There are 486 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA12	NM_173076.3	c.1765C>A	p.Pro589Thr	missense_variant	14/53	ENST00000272895.12	NP_775099.2
ABCA12	NM_015657.4	c.811C>A	p.Pro271Thr	missense_variant	6/45		NP_056472.2
ABCA12	XM_011510951.3	c.1765C>A	p.Pro589Thr	missense_variant	14/53		XP_011509253.1
ABCA12	NR_103740.2	n.2207C>A		non_coding_transcript_exon_variant	15/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA12	ENST00000272895.12	c.1765C>A	p.Pro589Thr	missense_variant	14/53	1	NM_173076.3	ENSP00000272895	P1
ABCA12	ENST00000389661.4	c.811C>A	p.Pro271Thr	missense_variant	6/45	1		ENSP00000374312
	ENST00000617699.1	n.278+276G>T		intron_variant, non_coding_transcript_variant		5
	ENST00000627811.1	n.73+4808G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00693 AC: 1055 AN: 152142 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00705 AC: 1773 AN: 251376 Hom.: 12 AF XY: 0.00694 AC XY: 943 AN XY: 135850

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.0112

Gnomad ASJ exome AF: 0.00317

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00962

GnomAD4 exome AF: 0.00927 AC: 13547 AN: 1461796 Hom.: 84 Cov.: 31 AF XY: 0.00895 AC XY: 6507 AN XY: 727196

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.0116

Gnomad4 ASJ exome AF: 0.00325

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.00191

Gnomad4 NFE exome AF: 0.0110

Gnomad4 OTH exome AF: 0.00848

GnomAD4 genome AF: 0.00692 AC: 1054 AN: 152260 Hom.: 6 Cov.: 33 AF XY: 0.00653 AC XY: 486 AN XY: 74444

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00935 Hom.: 10

Bravo AF: 0.00762

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0101 AC: 87

ExAC AF: 0.00683 AC: 829

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0120

EpiControl AF: 0.0115

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	ABCA12: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Congenital ichthyosis of skin Benign:1

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Autosomal recessive congenital ichthyosis 4B;C1832550:Autosomal recessive congenital ichthyosis 4A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.064
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	0.0070	T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	0.57	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.025	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.84	P;B
Vest4		0.60
MVP		0.78
MPC		0.24
ClinPred		0.036	T
GERP RS		5.0
Varity_R		0.13
gMVP		0.52

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: rs148979792; hg19: chr2-215882749;