NM_001606.5:c.7181G>A

Variant names:

• chr9-137008510-C-T
• rs55971316
• NM_001606.5:c.7181G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001606.5(ABCA2):​c.7181G>A​(p.Arg2394Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00118 in 1,586,100 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: ABCA2 NM_001606.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.86
• Publications: 5 publications found

Genes affected

ABCA2 (HGNC:32): (ATP binding cassette subfamily A member 2) 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, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This protein is highly expressed in brain tissue and may play a role in macrophage lipid metabolism and neural development. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ABCA2 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with poor growth and with or without seizures or ataxia

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• schizophrenia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042449564).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA2	NM_001606.5	c.7181G>A	p.Arg2394Gln	missense_variant	Exon 48 of 49	ENST00000341511.11	NP_001597.2
ABCA2	NM_212533.3	c.7271G>A	p.Arg2424Gln	missense_variant	Exon 48 of 49		NP_997698.1
ABCA2	NM_001411042.1	c.7178G>A	p.Arg2393Gln	missense_variant	Exon 47 of 48		NP_001397971.1
ABCA2	XM_047422921.1	c.7268G>A	p.Arg2423Gln	missense_variant	Exon 47 of 48		XP_047278877.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA2	ENST00000341511.11	c.7181G>A	p.Arg2394Gln	missense_variant	Exon 48 of 49	5	NM_001606.5	ENSP00000344155.6

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000609 AC: 123 AN: 202012 AF XY: 0.000621

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000200

Gnomad ASJ exome AF: 0.000109

Gnomad EAS exome AF: 0.000267

Gnomad FIN exome AF: 0.000118

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.000970

GnomAD4 exome AF: 0.00123 AC: 1766 AN: 1433768 Hom.: 3 Cov.: 42 AF XY: 0.00120 AC XY: 856 AN XY: 710598

African (AFR) AF: 0.0000303 AC: 1 AN: 33028

American (AMR) AF: 0.000343 AC: 14 AN: 40814

Ashkenazi Jewish (ASJ) AF: 0.0000390 AC: 1 AN: 25616

East Asian (EAS) AF: 0.000339 AC: 13 AN: 38354

South Asian (SAS) AF: 0.0000243 AC: 2 AN: 82468

European-Finnish (FIN) AF: 0.0000807 AC: 4 AN: 49590

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5738

European-Non Finnish (NFE) AF: 0.00149 AC: 1640 AN: 1098812

Other (OTH) AF: 0.00152 AC: 90 AN: 59348

GnomAD4 genome AF: 0.000735 AC: 112 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47 AN XY: 74482

African (AFR) AF: 0.000192 AC: 8 AN: 41574

American (AMR) AF: 0.000850 AC: 13 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00128 AC: 87 AN: 68030

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000889 Hom.: 0

Bravo AF: 0.000842

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00156 AC: 13

ExAC AF: 0.000461 AC: 55

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

May 13, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Jun 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2424 of the ABCA2 protein (p.Arg2424Gln). This variant is present in population databases (rs55971316, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ABCA2-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Jun 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7271G>A (p.R2424Q) alteration is located in exon 48 (coding exon 48) of the ABCA2 gene. This alteration results from a G to A substitution at nucleotide position 7271, causing the arginine (R) at amino acid position 2424 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	.;T;T;.;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.044
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.042	T;T;T;T;T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.8	.;L;.;.;.
PhyloP100		5.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.27	N;N;N;.;N
REVEL	Benign	0.28
Sift	Uncertain	0.029	D;D;D;.;D
Sift4G	Uncertain	0.022	D;D;D;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.47
MVP		0.72
MPC		0.78
ClinPred		0.081	T
GERP RS		3.8
Varity_R		0.18
gMVP		0.52
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55971316; hg19: chr9-139902962;