2-102473809-T-C

Position:

• chr2-102473809-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000295269.5(SLC9A4):​c.50T>C​(p.Leu17Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,614,132 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (48 hom.)
• Consequence: SLC9A4 ENST00000295269.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.714

Genes affected

SLC9A4 (HGNC:11077): (solute carrier family 9 member A4) 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 act upstream of or within epithelial cell development and gastric acid secretion. Predicted to be located in several cellular components, including apical plasma membrane; basolateral plasma membrane; and vacuolar 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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00512892).
• BP6: Variant 2-102473809-T-C is Benign according to our data. Variant chr2-102473809-T-C is described in ClinVar as [Benign]. Clinvar id is 791150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00219 (333/152352) while in subpopulation EAS AF= 0.0401 (208/5186). AF 95% confidence interval is 0.0356. There are 5 homozygotes in gnomad4. There are 166 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC9A4	NM_001011552.4	c.50T>C	p.Leu17Pro	missense_variant	1/12	ENST00000295269.5	NP_001011552.2
SLC9A4	XM_011511158.2	c.50T>C	p.Leu17Pro	missense_variant	1/12		XP_011509460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC9A4	ENST00000295269.5	c.50T>C	p.Leu17Pro	missense_variant	1/12	1	NM_001011552.4	ENSP00000295269	P1

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 331 AN: 152234 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0400

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00443 AC: 1113 AN: 251378 Hom.: 15 AF XY: 0.00366 AC XY: 497 AN XY: 135854

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.0135

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0324

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00178 AC: 2604 AN: 1461780 Hom.: 48 Cov.: 31 AF XY: 0.00162 AC XY: 1177 AN XY: 727196

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.0117

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0447

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.00407

GnomAD4 genome AF: 0.00219 AC: 333 AN: 152352 Hom.: 5 Cov.: 32 AF XY: 0.00223 AC XY: 166 AN XY: 74516

Gnomad4 AFR AF: 0.000793

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0401

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00158 Hom.: 7

Bravo AF: 0.00249

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00397 AC: 482

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 13, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.036
Eigen_PC	Benign	-0.078
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.22
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.046	D
Polyphen		0.80	P
Vest4		0.49
MVP		0.59
MPC		0.15
ClinPred		0.053	T
GERP RS		5.7
Varity_R		0.37
gMVP		0.85

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: rs79378995; hg19: chr2-103090268;