Genetic Variant SLC12A7:p.Ala963Ser (chr5-1057610-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006598.3(SLC12A7):c.2887G>T(p.Ala963Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,606,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A963V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

SLC12A7
NM_006598.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.121

Variant links:

Genes affected

SLC12A7 (HGNC:10915): (solute carrier family 12 member 7) Enables protein kinase binding activity. Predicted to be involved in several processes, including cell volume homeostasis; inorganic ion homeostasis; and inorganic ion transmembrane transport. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

SLC12A7 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.026716799).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A7	NM_006598.3 link	c.2887G>T	p.Ala963Ser	missense_variant	Exon 22 of 24	ENST00000264930.10	NP_006589.2	Q9Y666-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC12A7	ENST00000264930.10 link	c.2887G>T	p.Ala963Ser	missense_variant	Exon 22 of 24	1	NM_006598.3	ENSP00000264930.5	Q9Y666-1
SLC12A7	ENST00000634447.1 link	c.2587G>T	p.Ala863Ser	missense_variant	Exon 20 of 23	5		ENSP00000489285.1	A0A0U1RR18
SLC12A7	ENST00000513223.2 link	c.982G>T	p.Ala328Ser	missense_variant	Exon 8 of 8	5		ENSP00000428854.2	H0YB78
SLC12A7	ENST00000514994.1 link	n.187G>T		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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

GnomAD3 exomes

AF:

0.0000410

AC:

AN:

244160

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

132744

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000963

AC:

AN:

1453820

Hom.:

Cov.:

AF XY:

0.00000415

AC XY:

AN XY:

723530

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2887G>T (p.A963S) alteration is located in exon 22 (coding exon 22) of the SLC12A7 gene. This alteration results from a G to T substitution at nucleotide position 2887, causing the alanine (A) at amino acid position 963 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.60

CADD

Benign

1.1

DANN

Benign

0.30

DEOGEN2

Benign

0.18

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.55

M_CAP

Benign

0.013

MetaRNN

Benign

0.027

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PrimateAI

Benign

0.39

PROVEAN

Benign

0.19

REVEL

Benign

0.012

Sift

Benign

0.70

Sift4G

Benign

0.84

Polyphen

0.0010

Vest4

0.17

MutPred

0.18

Gain of glycosylation at A963 (P = 0.0051);

MVP

0.23

MPC

0.29

ClinPred

0.0067

GERP RS

1.3

Varity_R

0.030

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over