2-214990791-C-T

Variant names:

• chr2-214990791-C-T
• rs267606622
• NM_173076.3:c.3535G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_173076.3(ABCA12):​c.3535G>A​(p.Gly1179Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ABCA12 NM_173076.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.87
• Publications: 5 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 2-214990791-C-T is Pathogenic according to our data. Variant chr2-214990791-C-T is described in CliVar as Pathogenic. Clinvar id is 2863.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-214990791-C-T is described in CliVar as Pathogenic. Clinvar id is 2863.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-214990791-C-T is described in CliVar as Pathogenic. Clinvar id is 2863.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-214990791-C-T is described in CliVar as Pathogenic. Clinvar id is 2863.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA12	NM_173076.3	c.3535G>A	p.Gly1179Arg	missense_variant	Exon 24 of 53	ENST00000272895.12	NP_775099.2
ABCA12	NM_015657.4	c.2581G>A	p.Gly861Arg	missense_variant	Exon 16 of 45		NP_056472.2
ABCA12	XM_011510951.3	c.3535G>A	p.Gly1179Arg	missense_variant	Exon 24 of 53		XP_011509253.1
ABCA12	NR_103740.2	n.4033G>A		non_coding_transcript_exon_variant	Exon 26 of 55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA12	ENST00000272895.12	c.3535G>A	p.Gly1179Arg	missense_variant	Exon 24 of 53	1	NM_173076.3	ENSP00000272895.7
ABCA12	ENST00000389661.4	c.2581G>A	p.Gly861Arg	missense_variant	Exon 16 of 45	1		ENSP00000374312.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461824 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111970

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive congenital ichthyosis 4B Pathogenic:1

Nov 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.1	M;.
PhyloP100		7.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0060	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.91		Gain of methylation at G1179 (P = 0.0797);.;
MVP		0.95
MPC		0.81
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.91
gMVP		0.99
Mutation Taster		=6/94	disease causing (ClinVar)

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: rs267606622; hg19: chr2-215855515;