chr9-137007937-G-A

Variant names:

• chr9-137007937-G-A
• rs529532466
• NM_001606.5:c.7303C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001606.5(ABCA2):​c.7303C>T​(p.Leu2435Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,453,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: ABCA2 NM_001606.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• schizophrenia

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11246994).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001606.5. 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
	ABCA2	NM_001606.5	MANE Select	c.7303C>T	p.Leu2435Phe	missense	Exon 49 of 49	NP_001597.2
	ABCA2	NM_212533.3		c.7393C>T	p.Leu2465Phe	missense	Exon 49 of 49	NP_997698.1	Q9BZC7-4
	ABCA2	NM_001411042.1		c.7300C>T	p.Leu2434Phe	missense	Exon 48 of 48	NP_001397971.1	Q9BZC7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA2	ENST00000341511.11	TSL:5 MANE Select	c.7303C>T	p.Leu2435Phe	missense	Exon 49 of 49	ENSP00000344155.6	Q9BZC7-3
	ABCA2	ENST00000459850.5	TSL:1	n.7513C>T		non_coding_transcript_exon	Exon 47 of 47
	ABCA2	ENST00000479446.5	TSL:1	n.*1275C>T		non_coding_transcript_exon	Exon 35 of 35	ENSP00000420084.1	H0Y8D6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000619 AC: 15 AN: 242448 AF XY: 0.0000529

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000186 AC: 27 AN: 1453488 Hom.: 0 Cov.: 32 AF XY: 0.0000166 AC XY: 12 AN XY: 723314

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.000291 AC: 13 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5298

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111864

Other (OTH) AF: 0.0000332 AC: 2 AN: 60272

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000498 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.094
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.65	N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0050	B
Vest4		0.27
MutPred		0.14		Loss of helix (P = 0.1706)
MVP		0.55
MPC		0.74
ClinPred		0.18	T
GERP RS		3.6
Varity_R		0.13
gMVP		0.14
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs529532466; hg19: chr9-139902389; COSMIC: COSV55807162; COSMIC: COSV55807162;