rs56373660

Variant names:

• chr7-103389473-G-A
• rs56373660
• NM_198999.3:c.1312-49C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198999.3(SLC26A5):​c.1312-49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0827 in 1,361,026 control chromosomes in the GnomAD database, including 5,155 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (457 hom., cov: 32)
  • Exomes 𝑓: 0.084 (4698 hom.)
• Consequence: SLC26A5 NM_198999.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.110
• Publications: 5 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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 7-103389473-G-A is Benign according to our data. Variant chr7-103389473-G-A is described in ClinVar as Benign. ClinVar VariationId is 1239804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A5	NM_198999.3	c.1312-49C>T		intron_variant	Intron 12 of 19	ENST00000306312.8	NP_945350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A5	ENST00000306312.8	c.1312-49C>T		intron_variant	Intron 12 of 19	1	NM_198999.3	ENSP00000304783.3
SLC26A5	ENST00000393727.5	c.1312-49C>T		intron_variant	Intron 10 of 17	1		ENSP00000377328.1
SLC26A5	ENST00000393723.2	c.1312-359C>T		intron_variant	Intron 10 of 16	1		ENSP00000377324.1

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 10563 AN: 151948 Hom.: 459 Cov.: 32

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.0456

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.0943

Gnomad FIN AF: 0.0736

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.0804

Gnomad OTH AF: 0.0555

GnomAD2 exomes AF: 0.0913 AC: 22705 AN: 248672 AF XY: 0.0885

Gnomad AFR exome AF: 0.0211

Gnomad AMR exome AF: 0.177

Gnomad ASJ exome AF: 0.0461

Gnomad EAS exome AF: 0.115

Gnomad FIN exome AF: 0.0751

Gnomad NFE exome AF: 0.0768

Gnomad OTH exome AF: 0.0815

GnomAD4 exome AF: 0.0843 AC: 101944 AN: 1208958 Hom.: 4698 Cov.: 17 AF XY: 0.0840 AC XY: 51564 AN XY: 613998

African (AFR) AF: 0.0201 AC: 575 AN: 28616

American (AMR) AF: 0.174 AC: 7655 AN: 44082

Ashkenazi Jewish (ASJ) AF: 0.0445 AC: 1090 AN: 24502

East Asian (EAS) AF: 0.114 AC: 4400 AN: 38552

South Asian (SAS) AF: 0.0982 AC: 7945 AN: 80906

European-Finnish (FIN) AF: 0.0745 AC: 3948 AN: 53020

Middle Eastern (MID) AF: 0.0515 AC: 272 AN: 5284

European-Non Finnish (NFE) AF: 0.0815 AC: 71915 AN: 881866

Other (OTH) AF: 0.0795 AC: 4144 AN: 52130

GnomAD4 genome AF: 0.0695 AC: 10571 AN: 152068 Hom.: 457 Cov.: 32 AF XY: 0.0715 AC XY: 5311 AN XY: 74306

African (AFR) AF: 0.0226 AC: 938 AN: 41508

American (AMR) AF: 0.126 AC: 1928 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0456 AC: 158 AN: 3468

East Asian (EAS) AF: 0.113 AC: 582 AN: 5168

South Asian (SAS) AF: 0.0936 AC: 449 AN: 4798

European-Finnish (FIN) AF: 0.0736 AC: 777 AN: 10554

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0804 AC: 5464 AN: 67972

Other (OTH) AF: 0.0611 AC: 129 AN: 2112

Alfa AF: 0.0685 Hom.: 72

Bravo AF: 0.0714

Asia WGS AF: 0.146 AC: 508 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.5
DANN	Benign	0.82
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

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: rs56373660; hg19: chr7-103029920;