9-137008345-C-G

Variant names:

• chr9-137008345-C-G
• rs4880187
• ENST00000464157.1:n.336G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001606.5(ABCA2):​c.7275+71G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.958 in 1,525,942 control chromosomes in the GnomAD database, including 700,624 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (65974 hom., cov: 33)
  • Exomes 𝑓: 0.96 (634650 hom.)
• Consequence: ABCA2 NM_001606.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.49
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 9-137008345-C-G is Benign according to our data. Variant chr9-137008345-C-G is described in ClinVar as [Benign]. Clinvar id is 1185355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA2	NM_001606.5	c.7275+71G>C		intron_variant	Intron 48 of 48	ENST00000341511.11	NP_001597.2
ABCA2	NM_212533.3	c.7365+71G>C		intron_variant	Intron 48 of 48		NP_997698.1
ABCA2	NM_001411042.1	c.7272+71G>C		intron_variant	Intron 47 of 47		NP_001397971.1
ABCA2	XM_047422921.1	c.7362+71G>C		intron_variant	Intron 47 of 47		XP_047278877.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA2	ENST00000341511.11	c.7275+71G>C		intron_variant	Intron 48 of 48	5	NM_001606.5	ENSP00000344155.6

Frequencies

GnomAD3 genomes AF: 0.929 AC: 141339 AN: 152120 Hom.: 65941 Cov.: 33

Gnomad AFR AF: 0.833

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.962

Gnomad ASJ AF: 0.959

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.978

Gnomad FIN AF: 0.966

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.963

Gnomad OTH AF: 0.944

GnomAD2 exomes AF: 0.964 AC: 135526 AN: 140530 AF XY: 0.966

Gnomad AFR exome AF: 0.830

Gnomad AMR exome AF: 0.976

Gnomad ASJ exome AF: 0.963

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.973

Gnomad NFE exome AF: 0.964

Gnomad OTH exome AF: 0.967

GnomAD4 exome AF: 0.961 AC: 1320048 AN: 1373704 Hom.: 634650 Cov.: 27 AF XY: 0.961 AC XY: 652794 AN XY: 678944

African (AFR) AF: 0.828 AC: 25777 AN: 31148

American (AMR) AF: 0.975 AC: 34778 AN: 35676

Ashkenazi Jewish (ASJ) AF: 0.962 AC: 24099 AN: 25054

East Asian (EAS) AF: 1.00 AC: 35640 AN: 35642

South Asian (SAS) AF: 0.975 AC: 76773 AN: 78708

European-Finnish (FIN) AF: 0.971 AC: 40731 AN: 41928

Middle Eastern (MID) AF: 0.971 AC: 5495 AN: 5658

European-Non Finnish (NFE) AF: 0.962 AC: 1021819 AN: 1062548

Other (OTH) AF: 0.958 AC: 54936 AN: 57342

GnomAD4 genome AF: 0.929 AC: 141430 AN: 152238 Hom.: 65974 Cov.: 33 AF XY: 0.933 AC XY: 69452 AN XY: 74426

African (AFR) AF: 0.833 AC: 34563 AN: 41510

American (AMR) AF: 0.962 AC: 14716 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.959 AC: 3328 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5173 AN: 5176

South Asian (SAS) AF: 0.978 AC: 4718 AN: 4824

European-Finnish (FIN) AF: 0.966 AC: 10251 AN: 10612

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.963 AC: 65499 AN: 68022

Other (OTH) AF: 0.945 AC: 1995 AN: 2112

Alfa AF: 0.950 Hom.: 12085

Bravo AF: 0.925

Asia WGS AF: 0.976 AC: 3394 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual developmental disorder with poor growth and with or without seizures or ataxia Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.43
DANN	Benign	0.39
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs4880187; hg19: chr9-139902797; COSMIC: COSV55797106; COSMIC: COSV55797106;