rs17501837

Variant names:

• chr2-215037050-C-T
• rs17501837
• NM_173076.3:c.888G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_173076.3(ABCA12):​c.888G>A​(p.Val296Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,612,510 control chromosomes in the GnomAD database, including 37,283 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2995 hom., cov: 32)
  • Exomes 𝑓: 0.21 (34288 hom.)
• Consequence: ABCA12 NM_173076.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.189
• Publications: 12 publications found

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]

ABCA12 Gene-Disease associations (from GenCC):

• autosomal recessive congenital ichthyosis 4B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, PanelApp Australia, Orphanet, G2P
• autosomal recessive congenital ichthyosis 4A

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital non-bullous ichthyosiform erythroderma

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lamellar ichthyosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000227769 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-215037050-C-T is Benign according to our data. Variant chr2-215037050-C-T is described in ClinVar as Benign. ClinVar VariationId is 262834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.189 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173076.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA12	NM_173076.3	MANE Select	c.888G>A	p.Val296Val	synonymous	Exon 8 of 53	NP_775099.2
	ABCA12	NR_103740.2		n.1330G>A		non_coding_transcript_exon	Exon 9 of 55

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA12	ENST00000272895.12	TSL:1 MANE Select	c.888G>A	p.Val296Val	synonymous	Exon 8 of 53	ENSP00000272895.7
	ENSG00000227769	ENST00000419251.3	TSL:5	n.706+1217C>T		intron	N/A
	ENSG00000227769	ENST00000437897.7	TSL:5	n.1016+1217C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.191 AC: 29031 AN: 151974 Hom.: 3001 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.204

GnomAD2 exomes AF: 0.212 AC: 53177 AN: 251314 AF XY: 0.205

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.286

Gnomad ASJ exome AF: 0.193

Gnomad EAS exome AF: 0.395

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.201

Gnomad OTH exome AF: 0.206

GnomAD4 exome AF: 0.209 AC: 305910 AN: 1460418 Hom.: 34288 Cov.: 32 AF XY: 0.206 AC XY: 149795 AN XY: 726594

African (AFR) AF: 0.145 AC: 4842 AN: 33458

American (AMR) AF: 0.281 AC: 12571 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 5072 AN: 26120

East Asian (EAS) AF: 0.442 AC: 17538 AN: 39644

South Asian (SAS) AF: 0.130 AC: 11252 AN: 86236

European-Finnish (FIN) AF: 0.167 AC: 8927 AN: 53380

Middle Eastern (MID) AF: 0.149 AC: 859 AN: 5764

European-Non Finnish (NFE) AF: 0.209 AC: 232197 AN: 1110754

Other (OTH) AF: 0.210 AC: 12652 AN: 60354

GnomAD4 genome AF: 0.191 AC: 29029 AN: 152092 Hom.: 2995 Cov.: 32 AF XY: 0.190 AC XY: 14093 AN XY: 74358

African (AFR) AF: 0.147 AC: 6081 AN: 41480

American (AMR) AF: 0.220 AC: 3364 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 715 AN: 3470

East Asian (EAS) AF: 0.402 AC: 2075 AN: 5168

South Asian (SAS) AF: 0.132 AC: 638 AN: 4822

European-Finnish (FIN) AF: 0.167 AC: 1768 AN: 10560

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.201 AC: 13689 AN: 67996

Other (OTH) AF: 0.204 AC: 431 AN: 2108

Alfa AF: 0.202 Hom.: 8837

Bravo AF: 0.198

Asia WGS AF: 0.277 AC: 963 AN: 3478

EpiCase AF: 0.199

EpiControl AF: 0.201

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital ichthyosis of skin Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.6
DANN	Benign	0.70
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs17501837; hg19: chr2-215901774; COSMIC: COSV55952938; COSMIC: COSV55952938;