chr9-137018032-A-C

Variant names:

• chr9-137018032-A-C
• rs908832
• NM_001606.5:c.2037T>G

Variant summary

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

The NM_212533.3(ABCA2):​c.2127T>G​(p.Asp709Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as (no stars). Synonymous variant affecting the same amino acid position (i.e. D709D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCA2 NM_212533.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.603
• Publications: 30 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_212533.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA2	NM_001606.5	MANE Select	c.2037T>G	p.Asp679Glu	missense	Exon 15 of 49	NP_001597.2
	ABCA2	NM_212533.3		c.2127T>G	p.Asp709Glu	missense	Exon 15 of 49	NP_997698.1
	ABCA2	NM_001411042.1		c.2034T>G	p.Asp678Glu	missense	Exon 14 of 48	NP_001397971.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA2	ENST00000341511.11	TSL:5 MANE Select	c.2037T>G	p.Asp679Glu	missense	Exon 15 of 49	ENSP00000344155.6
	ABCA2	ENST00000459850.5	TSL:1	n.2167T>G		non_coding_transcript_exon	Exon 14 of 47
	ABCA2	ENST00000479446.5	TSL:1	n.84T>G		non_coding_transcript_exon	Exon 2 of 35	ENSP00000420084.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 84

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	17
DANN	Benign	0.47
DEOGEN2	Benign	0.30	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	0.012	D
MutationAssessor	Benign	0.51	N
PhyloP100		-0.60
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.30	N
REVEL	Uncertain	0.43
Sift	Benign	1.0	T
Sift4G	Benign	0.89	T
Polyphen		0.98	D
Vest4		0.51
MutPred		0.55		Loss of helix (P = 0.1299)
MVP		0.63
MPC		1.6
ClinPred		0.17	T
GERP RS		-2.8
Varity_R		0.20
gMVP		0.91
Mutation Taster		=77/23	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: rs908832; hg19: chr9-139912484;