20-49815040-A-C

Variant names:

• chr20-49815040-A-C
• rs750949529
• NM_015266.3:c.59A>C

Variant summary

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

The NM_015266.3(SLC9A8):​c.59A>C​(p.Asn20Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,448,092 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N20S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC9A8 NM_015266.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.19
• 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.59A>C	p.Asn20Thr	missense	Exon 2 of 16	NP_056081.1	Q9Y2E8-1
	SLC9A8	NM_001260491.2		c.59A>C	p.Asn20Thr	missense	Exon 2 of 16	NP_001247420.1	Q9Y2E8-2
	SLC9A8	NR_048537.2		n.154A>C		non_coding_transcript_exon	Exon 2 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A8	ENST00000361573.3	TSL:1 MANE Select	c.59A>C	p.Asn20Thr	missense	Exon 2 of 16	ENSP00000354966.2	Q9Y2E8-1
	SLC9A8	ENST00000851371.1		c.59A>C	p.Asn20Thr	missense	Exon 2 of 17	ENSP00000521430.1
	SLC9A8	ENST00000417961.5	TSL:2	c.59A>C	p.Asn20Thr	missense	Exon 2 of 16	ENSP00000416418.1	Q9Y2E8-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1448092 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 719698

African (AFR) AF: 0.00 AC: 0 AN: 32946

American (AMR) AF: 0.00 AC: 0 AN: 42646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25776

East Asian (EAS) AF: 0.00 AC: 0 AN: 38552

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105052

Other (OTH) AF: 0.00 AC: 0 AN: 59862

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.0063	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.056	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.69	N
PhyloP100		8.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.19
Sift	Benign	0.12	T
Sift4G	Benign	0.31	T
Polyphen		1.0	D
Vest4		0.53
MutPred		0.31		Gain of disorder (P = 0.089)
MVP		0.89
MPC		1.2
ClinPred		0.86	D
GERP RS		5.7
Varity_R		0.092
gMVP		0.43
Mutation Taster		=229/71	polymorphism

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

Other links and lift over

dbSNP: rs750949529; hg19: chr20-48431577;