9-137008538-C-G

Variant names:

• chr9-137008538-C-G
• rs748366859
• NM_001606.5:c.7153G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001606.5(ABCA2):​c.7153G>C​(p.Gly2385Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCA2 NM_001606.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.09
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21397063).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA2	NM_001606.5	c.7153G>C	p.Gly2385Arg	missense_variant	Exon 48 of 49	ENST00000341511.11	NP_001597.2
ABCA2	NM_212533.3	c.7243G>C	p.Gly2415Arg	missense_variant	Exon 48 of 49		NP_997698.1
ABCA2	NM_001411042.1	c.7150G>C	p.Gly2384Arg	missense_variant	Exon 47 of 48		NP_001397971.1
ABCA2	XM_047422921.1	c.7240G>C	p.Gly2414Arg	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.7153G>C	p.Gly2385Arg	missense_variant	Exon 48 of 49	5	NM_001606.5	ENSP00000344155.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7243G>C (p.G2415R) alteration is located in exon 48 (coding exon 48) of the ABCA2 gene. This alteration results from a G to C substitution at nucleotide position 7243, causing the glycine (G) at amino acid position 2415 to be replaced by an arginine (R). 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	0.11
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	14
DANN	Benign	0.56
DEOGEN2	Benign	0.28	.;T;T;.;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.69	T;T;T;T;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.21	T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.34	.;N;.;.;.
PhyloP100		1.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.32	N;N;N;.;N
REVEL	Benign	0.25
Sift	Benign	0.43	T;T;T;.;T
Sift4G	Benign	0.36	T;T;T;T;T
Polyphen		0.0020	.;B;.;.;.
Vest4		0.24
MutPred		0.41		.;Loss of sheet (P = 0.0011);.;.;.;
MVP		0.30
MPC		0.82
ClinPred		0.23	T
GERP RS		3.2
Varity_R		0.079
gMVP		0.30
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs748366859; hg19: chr9-139902990;