rs11890468

Positions:

• chr2-215045888-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173076.3(ABCA12):​c.821A>G​(p.Gln274Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00657 in 1,613,578 control chromosomes in the GnomAD database, including 570 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (294 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (276 hom.)
• Consequence: ABCA12 NM_173076.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.43

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=0.0015814602).
• BP6: Variant 2-215045888-T-C is Benign according to our data. Variant chr2-215045888-T-C is described in ClinVar as [Benign]. Clinvar id is 235321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA12	NM_173076.3	c.821A>G	p.Gln274Arg	missense_variant	7/53	ENST00000272895.12
ABCA12	XM_011510951.3	c.821A>G	p.Gln274Arg	missense_variant	7/53
ABCA12	NR_103740.2	n.1263A>G		non_coding_transcript_exon_variant	8/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA12	ENST00000272895.12	c.821A>G	p.Gln274Arg	missense_variant	7/53	1	NM_173076.3	P1
	ENST00000628464.2	n.1021+1371T>C		intron_variant, non_coding_transcript_variant		5
	ENST00000626134.2	n.404+1371T>C		intron_variant, non_coding_transcript_variant		5
	ENST00000626771.1	n.338+1371T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0349 AC: 5313 AN: 152166 Hom.: 292 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0171

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.0310

GnomAD3 exomes AF: 0.00923 AC: 2312 AN: 250430 Hom.: 128 AF XY: 0.00672 AC XY: 910 AN XY: 135364

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.00598

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000433

Gnomad OTH exome AF: 0.00623

GnomAD4 exome AF: 0.00361 AC: 5269 AN: 1461294 Hom.: 276 Cov.: 31 AF XY: 0.00304 AC XY: 2213 AN XY: 726960

Gnomad4 AFR exome AF: 0.120

Gnomad4 AMR exome AF: 0.00759

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000305

Gnomad4 OTH exome AF: 0.00835

GnomAD4 genome AF: 0.0350 AC: 5327 AN: 152284 Hom.: 294 Cov.: 32 AF XY: 0.0334 AC XY: 2489 AN XY: 74482

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0171

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.0307

Alfa AF: 0.00698 Hom.: 86

Bravo AF: 0.0414

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.126 AC: 557

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.0117 AC: 1423

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.000655

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 22, 2015	- -

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	0.073
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.90	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.031
Sift	Benign	0.072	T
Sift4G	Uncertain	0.018	D
Polyphen		0.0010	B
Vest4		0.050
MPC		0.20
ClinPred		0.0049	T
GERP RS		3.2
Varity_R		0.11
gMVP		0.42

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: rs11890468; hg19: chr2-215910612;