chr17-68868125-G-T

Variant names:

• chr17-68868125-G-T
• rs369120203
• NM_001288985.2:c.4826C>A

Variant summary

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

The NM_001288985.2(ABCA8):​c.4826C>A​(p.Pro1609His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ABCA8 NM_001288985.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05
• Publications: 0 publications found

Genes affected

ABCA8 (HGNC:38): (ATP binding cassette subfamily A member 8) 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. The encoded protein may regulate lipid metabolism and be involved in the formation and maintenance of myelin. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

LOC105371874 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.10785997).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001288985.2. 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
	ABCA8	NM_001288985.2	MANE Select	c.4826C>A	p.Pro1609His	missense	Exon 40 of 40	NP_001275914.1	O94911-3
	ABCA8	NM_001288986.2		c.4811C>A	p.Pro1604His	missense	Exon 39 of 39	NP_001275915.1	A0A0A0MSU4
	ABCA8	NM_007168.4		c.4706C>A	p.Pro1569His	missense	Exon 38 of 38	NP_009099.1	O94911-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA8	ENST00000586539.6	TSL:1 MANE Select	c.4826C>A	p.Pro1609His	missense	Exon 40 of 40	ENSP00000467271.1	O94911-3
	ABCA8	ENST00000430352.6	TSL:1	c.4811C>A	p.Pro1604His	missense	Exon 39 of 39	ENSP00000402814.3	A0A0A0MSU4
	ABCA8	ENST00000269080.6	TSL:1	c.4706C>A	p.Pro1569His	missense	Exon 38 of 38	ENSP00000269080.1	O94911-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000240 AC: 6 AN: 250086 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1460992 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726774

African (AFR) AF: 0.0000299 AC: 1 AN: 33442

American (AMR) AF: 0.000202 AC: 9 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111630

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74302

African (AFR) AF: 0.00 AC: 0 AN: 41418

American (AMR) AF: 0.0000656 AC: 1 AN: 15244

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.0
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.094
Sift	Benign	0.050	D
Sift4G	Benign	0.17	T
Polyphen		0.74	P
Vest4		0.11
MutPred		0.23		Gain of solvent accessibility (P = 0.0314)
MVP		0.48
MPC		0.093
ClinPred		0.37	T
GERP RS		-0.17
Varity_R		0.086
gMVP		0.19
Mutation Taster		=97/3	polymorphism

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: rs369120203; hg19: chr17-66864266;