NM_198999.3:c.498T>G

Variant names:

• chr7-103411492-A-C
• rs151200437
• NM_198999.3:c.498T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198999.3(SLC26A5):​c.498T>G​(p.Asn166Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N166N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC26A5 NM_198999.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.71
• Publications: 0 publications found

Genes affected

SLC26A5 (HGNC:9359): (solute carrier family 26 member 5) This gene encodes a member of the SLC26A/SulP transporter family. The protein functions as a molecular motor in motile outer hair cells (OHCs) of the cochlea, inducing changes in cell length that act to amplify sound levels. The transmembrane protein is an incomplete anion transporter, and does not allow anions to cross the cell membrane but instead undergoes a conformational change in response to changes in intracellular Cl- levels that results in a change in cell length. The protein functions at microsecond rates, which is several orders of magnitude faster than conventional molecular motor proteins. Mutations in this gene are potential candidates for causing neurosensory deafness. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2009]

SLC26A5 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 61

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2078703).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198999.3. 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
	SLC26A5	NM_198999.3	MANE Select	c.498T>G	p.Asn166Lys	missense	Exon 6 of 20	NP_945350.1	P58743-1
	SLC26A5	NM_001167962.2		c.498T>G	p.Asn166Lys	missense	Exon 6 of 19	NP_001161434.1	P58743-5
	SLC26A5	NM_206883.3		c.498T>G	p.Asn166Lys	missense	Exon 6 of 20	NP_996766.1	P58743-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A5	ENST00000306312.8	TSL:1 MANE Select	c.498T>G	p.Asn166Lys	missense	Exon 6 of 20	ENSP00000304783.3	P58743-1
	SLC26A5	ENST00000393727.5	TSL:1	c.498T>G	p.Asn166Lys	missense	Exon 4 of 18	ENSP00000377328.1	Q7Z7F4
	SLC26A5	ENST00000393723.2	TSL:1	c.498T>G	p.Asn166Lys	missense	Exon 4 of 17	ENSP00000377324.1	P58743-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	6.9
DANN	Uncertain	0.97
DEOGEN2	Pathogenic	0.84	D
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		-1.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.40
Sift	Benign	0.10	T
Sift4G	Benign	0.063	T
Polyphen		1.0	D
Vest4		0.32
MutPred		0.39		Gain of ubiquitination at N166 (P = 0.0104)
MVP		0.80
MPC		0.65
ClinPred		0.86	D
GERP RS		-2.8
Varity_R		0.21
gMVP		0.53
Mutation Taster		=46/54	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

dbSNP: rs151200437; hg19: chr7-103051939;