NM_015266.3:c.724G>A

Variant names:

• chr20-49862939-G-A
• NM_015266.3:c.724G>A

Variant summary

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

The NM_015266.3(SLC9A8):​c.724G>A​(p.Gly242Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,646 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SLC9A8 NM_015266.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.37
• 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.724G>A	p.Gly242Ser	missense	Exon 9 of 16	NP_056081.1	Q9Y2E8-1
	SLC9A8	NM_001260491.2		c.772G>A	p.Gly258Ser	missense	Exon 9 of 16	NP_001247420.1	Q9Y2E8-2
	SLC9A8	NR_048537.2		n.784G>A		non_coding_transcript_exon	Exon 8 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A8	ENST00000361573.3	TSL:1 MANE Select	c.724G>A	p.Gly242Ser	missense	Exon 9 of 16	ENSP00000354966.2	Q9Y2E8-1
	SLC9A8	ENST00000851371.1		c.823G>A	p.Gly275Ser	missense	Exon 10 of 17	ENSP00000521430.1
	SLC9A8	ENST00000417961.5	TSL:2	c.772G>A	p.Gly258Ser	missense	Exon 9 of 16	ENSP00000416418.1	Q9Y2E8-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459646 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 726180

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 85950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110376

Other (OTH) AF: 0.00 AC: 0 AN: 60344

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000455559), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

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	0.15
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.083
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.60	N
PhyloP100		9.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.28
Sift	Benign	0.69	T
Sift4G	Benign	0.61	T
Polyphen		0.15	B
Vest4		0.76
MutPred		0.37		Gain of disorder (P = 0.055)
MVP		0.50
MPC		0.45
ClinPred		0.95	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.76
Mutation Taster		=41/59	disease causing

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

hg19: chr20-48479476;