Genetic Variant SLC9C2:p.Val962Asp (chr1-173517559-A-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_178527.4(SLC9C2):c.2885T>A(p.Val962Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. V962A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SLC9C2
NM_178527.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.876

Publications

0 publications found

Variant links:

Genes affected

SLC9C2 (HGNC:28664): (solute carrier family 9 member C2 (putative)) Predicted to enable potassium:proton antiporter activity and sodium:proton antiporter activity. Predicted to be involved in potassium ion transmembrane transport; regulation of intracellular pH; and sodium ion import across plasma membrane. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLC9C2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.871

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178527.4. 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
	SLC9C2	NM_178527.4	MANE Select	c.2885T>A	p.Val962Asp	missense	Exon 23 of 28	NP_848622.2	Q5TAH2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9C2	ENST00000367714.4	TSL:1 MANE Select	c.2885T>A	p.Val962Asp	missense	Exon 23 of 28	ENSP00000356687.3	Q5TAH2
	SLC9C2	ENST00000466087.1	TSL:1	n.2219T>A		non_coding_transcript_exon	Exon 16 of 21

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1457052

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724630

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33124

American (AMR)

AF:

0.00

AC:

AN:

43500

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25946

East Asian (EAS)

AF:

0.00

AC:

AN:

39560

South Asian (SAS)

AF:

0.00

AC:

AN:

84936

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53310

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110704

Other (OTH)

AF:

0.00

AC:

AN:

60220

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Uncertain

0.71

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.73

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.87

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

0.69

PhyloP100

0.88

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0060

Polyphen

0.29

Vest4

0.85

MutPred

0.68

Loss of sheet (P = 0.007)

MVP

0.54

MPC

0.49

ClinPred

0.41

GERP RS

3.1

Varity_R

0.67

gMVP

0.95

Mutation Taster

=96/4

polymorphism

(source)

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over