chr20-49850842-C-G

Variant names:

• chr20-49850842-C-G
• rs747968361
• NM_015266.3:c.567C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015266.3(SLC9A8):​c.567C>G​(p.Asp189Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000622 in 1,606,940 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SLC9A8 NM_015266.3 missense, splice_region
• Scores: Splicing: ADA: 0.01354
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.52
• Publications: 0 publications found

Genes affected

SLC9A8 (HGNC:20728): (solute carrier family 9 member A8) Sodium-hydrogen exchangers (NHEs), such as SLC9A8, are integral transmembrane proteins that exchange extracellular Na+ for intracellular H+. NHEs have multiple functions, including intracellular pH homeostasis, cell volume regulation, and electroneutral NaCl absorption in epithelia (Xu et al., 2008 [PubMed 18209477]).[supplied by OMIM, Apr 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015266.3. 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
	SLC9A8	NM_015266.3	MANE Select	c.567C>G	p.Asp189Glu	missense splice_region	Exon 7 of 16	NP_056081.1	Q9Y2E8-1
	SLC9A8	NM_001260491.2		c.615C>G	p.Asp205Glu	missense splice_region	Exon 7 of 16	NP_001247420.1	Q9Y2E8-2
	SLC9A8	NR_048537.2		n.629+1162C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A8	ENST00000361573.3	TSL:1 MANE Select	c.567C>G	p.Asp189Glu	missense splice_region	Exon 7 of 16	ENSP00000354966.2	Q9Y2E8-1
	SLC9A8	ENST00000851371.1		c.567C>G	p.Asp189Glu	missense splice_region	Exon 7 of 17	ENSP00000521430.1
	SLC9A8	ENST00000417961.5	TSL:2	c.615C>G	p.Asp205Glu	missense splice_region	Exon 7 of 16	ENSP00000416418.1	Q9Y2E8-2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151948 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000478

GnomAD2 exomes AF: 0.00000407 AC: 1 AN: 245574 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1454992 Hom.: 0 Cov.: 30 AF XY: 0.00000553 AC XY: 4 AN XY: 723586

African (AFR) AF: 0.00 AC: 0 AN: 33068

American (AMR) AF: 0.0000687 AC: 3 AN: 43654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 84312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109060

Other (OTH) AF: 0.0000166 AC: 1 AN: 60132

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151948 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74210

African (AFR) AF: 0.00 AC: 0 AN: 41348

American (AMR) AF: 0.000262 AC: 4 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Benign	0.74
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.035
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.94	N
PhyloP100		4.5
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	1.1	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.033	B
Vest4		0.88
MutPred		0.60		Gain of sheet (P = 0.0073)
MVP		0.35
MPC		0.35
ClinPred		0.23	T
GERP RS		5.7
Varity_R		0.21
gMVP		0.65
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs747968361; hg19: chr20-48467379;