rs148979792

Variant names:

• chr2-215018025-G-T
• rs148979792
• NM_173076.3:c.1765C>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.1765C>A​(p.Pro589Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00905 in 1,614,056 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P589R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0069 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0093 (84 hom.)
• Consequence: ABCA12 NM_173076.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.56
• 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: G2P, Genomics England PanelApp, Orphanet
• autosomal recessive congenital ichthyosis 4A

  Inheritance: AR Classification: STRONG Submitted by: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006954968).
• BP6: Variant 2-215018025-G-T is Benign according to our data. Variant chr2-215018025-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262821.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 = 0.00692 (1054/152260) while in subpopulation AMR AF = 0.0127 (194/15294). AF 95% confidence interval is 0.0112. There are 6 homozygotes in GnomAd4. There are 486 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.1765C>A	p.Pro589Thr	missense	Exon 14 of 53	NP_775099.2
	ABCA12	NM_015657.4		c.811C>A	p.Pro271Thr	missense	Exon 6 of 45	NP_056472.2
	ABCA12	NR_103740.2		n.2207C>A		non_coding_transcript_exon	Exon 15 of 55

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA12	ENST00000272895.12	TSL:1 MANE Select	c.1765C>A	p.Pro589Thr	missense	Exon 14 of 53	ENSP00000272895.7	Q86UK0-1
	ABCA12	ENST00000389661.4	TSL:1	c.811C>A	p.Pro271Thr	missense	Exon 6 of 45	ENSP00000374312.4	Q86UK0-2
	ENSG00000227769	ENST00000617699.1	TSL:5	n.278+276G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00693 AC: 1055 AN: 152142 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00705 AC: 1773 AN: 251376 AF XY: 0.00694

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.0112

Gnomad ASJ exome AF: 0.00317

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00962

GnomAD4 exome AF: 0.00927 AC: 13547 AN: 1461796 Hom.: 84 Cov.: 31 AF XY: 0.00895 AC XY: 6507 AN XY: 727196

African (AFR) AF: 0.00164 AC: 55 AN: 33480

American (AMR) AF: 0.0116 AC: 521 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00325 AC: 85 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.000499 AC: 43 AN: 86258

European-Finnish (FIN) AF: 0.00191 AC: 102 AN: 53380

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.0110 AC: 12198 AN: 1111980

Other (OTH) AF: 0.00848 AC: 512 AN: 60390

GnomAD4 genome AF: 0.00692 AC: 1054 AN: 152260 Hom.: 6 Cov.: 33 AF XY: 0.00653 AC XY: 486 AN XY: 74444

African (AFR) AF: 0.00214 AC: 89 AN: 41556

American (AMR) AF: 0.0127 AC: 194 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3468

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

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0105 AC: 711 AN: 68020

Other (OTH) AF: 0.0132 AC: 28 AN: 2116

Alfa AF: 0.00901 Hom.: 16

Bravo AF: 0.00762

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0101 AC: 87

ExAC AF: 0.00683 AC: 829

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0120

EpiControl AF: 0.0115

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal recessive congenital ichthyosis 4B;C1832550:Autosomal recessive congenital ichthyosis 4A (1)
-	-	1	Congenital ichthyosis of skin (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.064
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.6
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.84	P
Vest4		0.60
MVP		0.78
MPC		0.24
ClinPred		0.036	T
GERP RS		5.0
Varity_R		0.13
gMVP		0.52
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: rs148979792; hg19: chr2-215882749; COSMIC: COSV106085112; COSMIC: COSV106085112;