1-173521318-T-C

Variant names:

• chr1-173521318-T-C
• rs780625309
• NM_178527.4:c.2722A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_178527.4(SLC9C2):​c.2722A>G​(p.Ile908Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000654 in 1,375,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: SLC9C2 NM_178527.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28541547).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC9C2	NM_178527.4	c.2722A>G	p.Ile908Val	missense_variant	Exon 22 of 28	ENST00000367714.4	NP_848622.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC9C2	ENST00000367714.4	c.2722A>G	p.Ile908Val	missense_variant	Exon 22 of 28	1	NM_178527.4	ENSP00000356687.3
SLC9C2	ENST00000466087.1	n.2056A>G		non_coding_transcript_exon_variant	Exon 15 of 21	1
SLC9C2	ENST00000648789.1	n.1327A>G		non_coding_transcript_exon_variant	Exon 11 of 11

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000532 AC: 1 AN: 188060 Hom.: 0 AF XY: 0.00000965 AC XY: 1 AN XY: 103612

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000107

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000654 AC: 9 AN: 1375802 Hom.: 0 Cov.: 29 AF XY: 0.00000439 AC XY: 3 AN XY: 683842

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000836

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2722A>G (p.I908V) alteration is located in exon 22 (coding exon 21) of the SLC9C2 gene. This alteration results from a A to G substitution at nucleotide position 2722, causing the isoleucine (I) at amino acid position 908 to be replaced by a valine (V). 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	0.12
BayesDel_addAF	Benign	-0.0064	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.017
Eigen_PC	Benign	0.046
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	-0.067	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.42	N
REVEL	Uncertain	0.41
Sift	Benign	0.080	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.91	P
Vest4		0.14
MutPred		0.69		Loss of sheet (P = 0.0228);
MVP		0.68
MPC		0.62
ClinPred		0.43	T
GERP RS		4.1
Varity_R		0.040
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs780625309; hg19: chr1-173490457;