rs114258385

Variant names:

• chr2-214970346-C-T
• rs114258385
• NM_173076.3:c.5617G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173076.3(ABCA12):​c.5617G>A​(p.Val1873Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,612,944 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V1873V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0071 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (9 hom.)
• Consequence: ABCA12 NM_173076.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0940
• Publications: 3 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039067864).
• BP6: Variant 2-214970346-C-T is Benign according to our data. Variant chr2-214970346-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00706 (1074/152098) while in subpopulation AFR AF = 0.0249 (1035/41514). AF 95% confidence interval is 0.0237. There are 17 homozygotes in GnomAd4. There are 508 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA12	NM_173076.3	MANE Select	c.5617G>A	p.Val1873Ile	missense	Exon 37 of 53	NP_775099.2
	ABCA12	NM_015657.4		c.4663G>A	p.Val1555Ile	missense	Exon 29 of 45	NP_056472.2
	ABCA12	NR_103740.2		n.6115G>A		non_coding_transcript_exon	Exon 39 of 55

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA12	ENST00000272895.12	TSL:1 MANE Select	c.5617G>A	p.Val1873Ile	missense	Exon 37 of 53	ENSP00000272895.7
	ABCA12	ENST00000389661.4	TSL:1	c.4663G>A	p.Val1555Ile	missense	Exon 29 of 45	ENSP00000374312.4

Frequencies

GnomAD3 genomes AF: 0.00703 AC: 1068 AN: 151980 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00189 AC: 473 AN: 250838 AF XY: 0.00134

Gnomad AFR exome AF: 0.0252

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000741 AC: 1083 AN: 1460846 Hom.: 9 Cov.: 31 AF XY: 0.000665 AC XY: 483 AN XY: 726746

African (AFR) AF: 0.0256 AC: 857 AN: 33426

American (AMR) AF: 0.00134 AC: 60 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5754

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1111324

Other (OTH) AF: 0.00156 AC: 94 AN: 60340

GnomAD4 genome AF: 0.00706 AC: 1074 AN: 152098 Hom.: 17 Cov.: 32 AF XY: 0.00683 AC XY: 508 AN XY: 74374

African (AFR) AF: 0.0249 AC: 1035 AN: 41514

American (AMR) AF: 0.00138 AC: 21 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67934

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00289 Hom.: 7

Bravo AF: 0.00833

ESP6500AA AF: 0.0241 AC: 106

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00228 AC: 277

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Congenital ichthyosis of skin (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.9
DANN	Benign	0.51
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.51	N
PhyloP100		0.094
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.28
Sift	Benign	0.68	T
Sift4G	Benign	0.52	T
Polyphen		0.0010	B
Vest4		0.054
MVP		0.55
MPC		0.15
ClinPred		0.0021	T
GERP RS		1.4
Varity_R		0.023
gMVP		0.27
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs114258385; hg19: chr2-215835070; COSMIC: COSV99078585;