NM_001606.5:c.1193C>A

Variant names:

• chr9-137020766-G-T
• rs143473036
• NM_001606.5:c.1193C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001606.5(ABCA2):​c.1193C>A​(p.Thr398Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,596,662 control chromosomes in the GnomAD database, including 10 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T398T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: ABCA2 NM_001606.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.234
• Publications: 3 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004522741).
• BP6: Variant 9-137020766-G-T is Benign according to our data. Variant chr9-137020766-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 522833.
• BS2: High Homozygotes in GnomAd4 at 2 AR,Unknown gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA2	NM_001606.5	MANE Select	c.1193C>A	p.Thr398Lys	missense	Exon 9 of 49	NP_001597.2
	ABCA2	NM_212533.3		c.1283C>A	p.Thr428Lys	missense	Exon 9 of 49	NP_997698.1
	ABCA2	NM_001411042.1		c.1190C>A	p.Thr397Lys	missense	Exon 8 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.1193C>A	p.Thr398Lys	missense	Exon 9 of 49	ENSP00000344155.6
	ABCA2	ENST00000459850.5	TSL:1	n.1323C>A		non_coding_transcript_exon	Exon 8 of 47
	ABCA2	ENST00000487109.5	TSL:1	n.1280C>A		non_coding_transcript_exon	Exon 8 of 47	ENSP00000418662.1

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 236 AN: 152240 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000564

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00276

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00175 AC: 386 AN: 220462 AF XY: 0.00198

Gnomad AFR exome AF: 0.000393

Gnomad AMR exome AF: 0.000487

Gnomad ASJ exome AF: 0.000212

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000633

Gnomad NFE exome AF: 0.00297

Gnomad OTH exome AF: 0.00109

GnomAD4 exome AF: 0.00268 AC: 3871 AN: 1444304 Hom.: 8 Cov.: 31 AF XY: 0.00265 AC XY: 1902 AN XY: 717860

African (AFR) AF: 0.000361 AC: 12 AN: 33264

American (AMR) AF: 0.000709 AC: 31 AN: 43704

Ashkenazi Jewish (ASJ) AF: 0.000193 AC: 5 AN: 25868

East Asian (EAS) AF: 0.00 AC: 0 AN: 39184

South Asian (SAS) AF: 0.00192 AC: 163 AN: 85022

European-Finnish (FIN) AF: 0.000334 AC: 15 AN: 44920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00321 AC: 3548 AN: 1106844

Other (OTH) AF: 0.00162 AC: 97 AN: 59752

GnomAD4 genome AF: 0.00155 AC: 236 AN: 152358 Hom.: 2 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74504

African (AFR) AF: 0.000361 AC: 15 AN: 41574

American (AMR) AF: 0.000718 AC: 11 AN: 15314

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4830

European-Finnish (FIN) AF: 0.000564 AC: 6 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00276 AC: 188 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00127 Hom.: 0

Bravo AF: 0.00160

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000251 AC: 1

ESP6500EA AF: 0.00330 AC: 27

ExAC AF: 0.00196 AC: 233

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

ABCA2-related disorder Uncertain:1 Benign:1

Nov 08, 2017

Undiagnosed Diseases Network, NIH

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 01, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

not provided Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCA2: PP2, BS2

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.35
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0066	N
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.23
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.23
Sift	Benign	0.51	T
Sift4G	Benign	0.94	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.62
MPC		0.52
ClinPred		0.0054	T
GERP RS		-3.0
Varity_R		0.019
gMVP		0.69
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs143473036; hg19: chr9-139915218; COSMIC: COSV106081515; COSMIC: COSV106081515;