Genetic Variant SLC9A8:p.Val285Leu (chr20-49864739-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015266.3(SLC9A8):c.853G>T(p.Val285Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,460,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V285M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC9A8
NM_015266.3 missense, splice_region

Scores

Splicing: ADA: 0.002020

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.93

Publications

0 publications found

Variant links:

Genes affected

SLC9A8 (HGNC:20728): (solute carrier family 9 member A8) Sodium-hydrogen exchangers (NHEs), such as SLC9A8, are integral transmembrane proteins that exchange extracellular Na+ for intracellular H+. NHEs have multiple functions, including intracellular pH homeostasis, cell volume regulation, and electroneutral NaCl absorption in epithelia (Xu et al., 2008 [PubMed 18209477]).[supplied by OMIM, Apr 2009]

SLC9A8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12286791).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015266.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC9A8	NM_015266.3	MANE Select	c.853G>T	p.Val285Leu	missense splice_region	Exon 10 of 16	NP_056081.1	Q9Y2E8-1
SLC9A8	NM_001260491.2		c.901G>T	p.Val301Leu	missense splice_region	Exon 10 of 16	NP_001247420.1	Q9Y2E8-2
SLC9A8	NR_048537.2		n.913G>T		splice_region non_coding_transcript_exon	Exon 9 of 15

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC9A8	ENST00000361573.3	TSL:1 MANE Select	c.853G>T	p.Val285Leu	missense splice_region	Exon 10 of 16	ENSP00000354966.2	Q9Y2E8-1
SLC9A8	ENST00000851371.1		c.952G>T	p.Val318Leu	missense splice_region	Exon 11 of 17	ENSP00000521430.1
SLC9A8	ENST00000417961.5	TSL:2	c.901G>T	p.Val301Leu	missense splice_region	Exon 10 of 16	ENSP00000416418.1	Q9Y2E8-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460000

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726442

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33424

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110330

Other (OTH)

AF:

0.00

AC:

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.033

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.0055

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

PhyloP100

4.9

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

0.93

REVEL

Benign

0.11

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.37

MutPred

0.68

Gain of helix (P = 0.0854)

MVP

0.27

MPC

0.37

ClinPred

0.30

GERP RS

4.3

Varity_R

0.081

gMVP

0.58

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0020

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over