9-137020766-G-T

Position:

• chr9-137020766-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ABCA2. . Gene score misZ 4.9116 (greater than the threshold 3.09). Trascript score misZ 3.725 (greater than threshold 3.09). GenCC has associacion of gene with schizophrenia, intellectual developmental disorder with poor growth and with or without seizures or ataxia.
• 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 id is 522833.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA2	NM_001606.5	c.1193C>A	p.Thr398Lys	missense_variant	9/49	ENST00000341511.11	NP_001597.2
ABCA2	NM_212533.3	c.1283C>A	p.Thr428Lys	missense_variant	9/49		NP_997698.1
ABCA2	NM_001411042.1	c.1190C>A	p.Thr397Lys	missense_variant	8/48		NP_001397971.1
ABCA2	XM_047422921.1	c.1280C>A	p.Thr427Lys	missense_variant	8/48		XP_047278877.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA2	ENST00000341511.11	c.1193C>A	p.Thr398Lys	missense_variant	9/49	5	NM_001606.5	ENSP00000344155	P3

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

GnomAD3 exomes AF: 0.00175 AC: 386 AN: 220462 Hom.: 0 AF XY: 0.00198 AC XY: 242 AN XY: 122344

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 SAS exome AF: 0.00176

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

Gnomad4 AFR exome AF: 0.000361

Gnomad4 AMR exome AF: 0.000709

Gnomad4 ASJ exome AF: 0.000193

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00192

Gnomad4 FIN exome AF: 0.000334

Gnomad4 NFE exome AF: 0.00321

Gnomad4 OTH exome AF: 0.00162

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

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.000564

Gnomad4 NFE AF: 0.00276

Gnomad4 OTH AF: 0.00189

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

Uncertain significance, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Nov 08, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 01, 2022	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

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	ABCA2: PP2, BS2 -

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0066	N
LIST_S2	Benign	0.69	T;T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.0045	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.69	.;N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.53	N;N;N;.
REVEL	Benign	0.23
Sift	Benign	0.51	T;T;T;.
Sift4G	Benign	0.94	T;T;T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs143473036; hg19: chr9-139915218;