Genetic Variant SLC9C2:p.Leu885His (chr1-173521386-A-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_178527.4(SLC9C2):c.2654T>A(p.Leu885His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000567 in 1,515,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

SLC9C2
NM_178527.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.32

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.772

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.2654T>A	p.Leu885His	missense	Exon 22 of 28	NP_848622.2	Q5TAH2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC9C2	ENST00000367714.4	TSL:1 MANE Select	c.2654T>A	p.Leu885His	missense	Exon 22 of 28	ENSP00000356687.3	Q5TAH2
SLC9C2	ENST00000466087.1	TSL:1	n.1988T>A		non_coding_transcript_exon	Exon 15 of 21
SLC9C2	ENST00000648789.1		n.1259T>A		non_coding_transcript_exon	Exon 11 of 11

Frequencies

GnomAD3 genomes

AF:

0.0000200

AC:

AN:

150362

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000443

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000216

AC:

AN:

185006

AF XY:

0.0000293

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000435

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000608

AC:

AN:

1365272

Hom.:

Cov.:

AF XY:

0.0000561

AC XY:

AN XY:

677902

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28372

American (AMR)

AF:

0.00

AC:

AN:

27548

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23264

East Asian (EAS)

AF:

0.00

AC:

AN:

35320

South Asian (SAS)

AF:

0.00

AC:

AN:

67516

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5448

European-Non Finnish (NFE)

AF:

0.0000691

AC:

AN:

1071208

Other (OTH)

AF:

0.000161

AC:

AN:

55974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

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

AF:

0.0000200

AC:

AN:

150362

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73352

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41120

American (AMR)

AF:

0.00

AC:

AN:

15094

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9774

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000443

AC:

AN:

67650

Other (OTH)

AF:

0.00

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000847

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.089

Eigen

Benign

0.15

Eigen_PC

Benign

0.044

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.53

M_CAP

Benign

0.025

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.5

PhyloP100

3.3

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.58

MVP

0.54

MPC

0.97

ClinPred

0.97

GERP RS

4.1

Varity_R

0.47

gMVP

0.58

Mutation Taster

=97/3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over