rs76979001

chr2-215015554-C-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.1892G>A(p.Arg631Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,614,026 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R631W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (42 hom.)
• Consequence: ABCA12 NM_173076.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.519

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=0.0032784045).
• BP6: Variant 2-215015554-C-T is Benign according to our data. Variant chr2-215015554-C-T is described in ClinVar as [Benign]. Clinvar id is 262822.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 = 0.00274 (417/152224) while in subpopulation AMR AF= 0.0153 (234/15294). AF 95% confidence interval is 0.0137. There are 3 homozygotes in gnomad4. There are 235 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA12	NM_173076.3	c.1892G>A	p.Arg631Gln	missense_variant	15/53	ENST00000272895.12
ABCA12	NM_015657.4	c.938G>A	p.Arg313Gln	missense_variant	7/45
ABCA12	XM_011510951.3	c.1892G>A	p.Arg631Gln	missense_variant	15/53
ABCA12	NR_103740.2	n.2334G>A		non_coding_transcript_exon_variant	16/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA12	ENST00000272895.12	c.1892G>A	p.Arg631Gln	missense_variant	15/53	1	NM_173076.3	P1
ABCA12	ENST00000389661.4	c.938G>A	p.Arg313Gln	missense_variant	7/45	1
	ENST00000617699.1	n.191-2108C>T		intron_variant, non_coding_transcript_variant		5
	ENST00000627811.1	n.73+2337C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 413 AN: 152106 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0120

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00774

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00669 AC: 1682 AN: 251296 Hom.: 41 AF XY: 0.00540 AC XY: 734 AN XY: 135826

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.0383

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0116

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00448

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00174 AC: 2540 AN: 1461802 Hom.: 42 Cov.: 31 AF XY: 0.00161 AC XY: 1169 AN XY: 727200

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.0359

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0137

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00384

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00274 AC: 417 AN: 152224 Hom.: 3 Cov.: 31 AF XY: 0.00316 AC XY: 235 AN XY: 74428

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.0153

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0122

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00774

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000761 Hom.: 3

Bravo AF: 0.00479

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00525 AC: 637

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Congenital ichthyosis of skin Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	8.4
Dann	Benign	0.95
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.44	T;T
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.66	N;N
REVEL	Benign	0.14
Sift	Benign	0.20	T;T
Sift4G	Uncertain	0.024	D;T
Polyphen		0.41	B;B
Vest4		0.23
MVP		0.66
MPC		0.26
ClinPred		0.0024	T
GERP RS		2.4
Varity_R		0.024
gMVP		0.34

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: rs76979001; hg19: chr2-215880278; COSMIC: COSV55952921; COSMIC: COSV55952921;