9-104858586-C-T

Variant names:

• chr9-104858586-C-T
• rs2230806
• NM_005502.4:c.656G>A

Variant summary

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

The NM_005502.4(ABCA1):​c.656G>A​(p.Arg219Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,613,856 control chromosomes in the GnomAD database, including 80,178 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R219R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.38 (13060 hom., cov: 33)
  • Exomes 𝑓: 0.29 (67118 hom.)
• Consequence: ABCA1 NM_005502.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.545
• Publications: 283 publications found

Genes affected

ABCA1 (HGNC:29): (ATP binding cassette subfamily A member 1) 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. With cholesterol as its substrate, this protein functions as a cholesteral efflux pump in the cellular lipid removal pathway. Mutations in both alleles of this gene cause Tangier disease and familial high-density lipoprotein (HDL) deficiency. [provided by RefSeq, Sep 2019]

ABCA1 Gene-Disease associations (from GenCC):

• hypoalphalipoproteinemia, primary, 1

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Tangier disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• apolipoprotein A-I deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2091895E-5).
• BP6: Variant 9-104858586-C-T is Benign according to our data. Variant chr9-104858586-C-T is described in ClinVar as Benign. ClinVar VariationId is 9506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA1	NM_005502.4	c.656G>A	p.Arg219Lys	missense_variant	Exon 7 of 50	ENST00000374736.8	NP_005493.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA1	ENST00000374736.8	c.656G>A	p.Arg219Lys	missense_variant	Exon 7 of 50	1	NM_005502.4	ENSP00000363868.3
ABCA1	ENST00000678995.1	c.656G>A	p.Arg219Lys	missense_variant	Exon 7 of 50			ENSP00000504612.1
ABCA1	ENST00000423487.6	c.656G>A	p.Arg219Lys	missense_variant	Exon 7 of 8	2		ENSP00000416623.2

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58319 AN: 151970 Hom.: 13020 Cov.: 33

Gnomad AFR AF: 0.625

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.377

GnomAD2 exomes AF: 0.324 AC: 81377 AN: 251448 AF XY: 0.320

Gnomad AFR exome AF: 0.630

Gnomad AMR exome AF: 0.325

Gnomad ASJ exome AF: 0.281

Gnomad EAS exome AF: 0.431

Gnomad FIN exome AF: 0.220

Gnomad NFE exome AF: 0.274

Gnomad OTH exome AF: 0.318

GnomAD4 exome AF: 0.293 AC: 428401 AN: 1461766 Hom.: 67118 Cov.: 42 AF XY: 0.295 AC XY: 214422 AN XY: 727200

African (AFR) AF: 0.647 AC: 21668 AN: 33476

American (AMR) AF: 0.328 AC: 14667 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 7337 AN: 26136

East Asian (EAS) AF: 0.472 AC: 18746 AN: 39698

South Asian (SAS) AF: 0.368 AC: 31746 AN: 86256

European-Finnish (FIN) AF: 0.220 AC: 11768 AN: 53412

Middle Eastern (MID) AF: 0.404 AC: 2331 AN: 5766

European-Non Finnish (NFE) AF: 0.271 AC: 300877 AN: 1111908

Other (OTH) AF: 0.319 AC: 19261 AN: 60390

GnomAD4 genome AF: 0.384 AC: 58426 AN: 152090 Hom.: 13060 Cov.: 33 AF XY: 0.382 AC XY: 28416 AN XY: 74352

African (AFR) AF: 0.626 AC: 25941 AN: 41464

American (AMR) AF: 0.346 AC: 5288 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 959 AN: 3470

East Asian (EAS) AF: 0.427 AC: 2208 AN: 5176

South Asian (SAS) AF: 0.372 AC: 1796 AN: 4822

European-Finnish (FIN) AF: 0.222 AC: 2347 AN: 10580

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.273 AC: 18555 AN: 67986

Other (OTH) AF: 0.382 AC: 808 AN: 2116

Alfa AF: 0.315 Hom.: 34779

Bravo AF: 0.404

TwinsUK AF: 0.259 AC: 959

ALSPAC AF: 0.268 AC: 1032

ESP6500AA AF: 0.606 AC: 2672

ESP6500EA AF: 0.281 AC: 2420

ExAC AF: 0.330 AC: 40042

Asia WGS AF: 0.423 AC: 1471 AN: 3478

EpiCase AF: 0.288

EpiControl AF: 0.283

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20170916, 21310416, 18927311, 12700893, 21643759, 20797885, 20346718, 21300560, 18621447, 19304534, 17407076, 11238261, 24157307, 26243156, 31006134, 25104170, 24466114, 27560308) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tangier disease Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RECLASSIFIED - ABCA1 POLYMORPHISM Benign:1

Jan 01, 2006

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cardiovascular phenotype Benign:1

Dec 11, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hypoalphalipoproteinemia, primary, 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	6.2
DANN	Benign	0.83
DEOGEN2	Benign	0.24	T;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.37	T;T
MetaRNN	Benign	0.000012	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.11	N;.
PhyloP100		0.55
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.010	N;N
REVEL	Benign	0.19
Sift	Benign	0.62	T;T
Sift4G	Benign	0.92	T;T
Polyphen		0.0	B;.
Vest4		0.041
MPC		0.18
ClinPred		0.00098	T
GERP RS		0.057
Varity_R		0.10
gMVP		0.089
Mutation Taster		=96/4	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: rs2230806; hg19: chr9-107620867; COSMIC: COSV66057914; COSMIC: COSV66057914;