chr7-103376701-A-G

Variant names:

• chr7-103376701-A-G
• rs72655393
• NM_198999.3:c.2041+107T>C

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.2041+107T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00522 in 889,448 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (102 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (48 hom.)
• Consequence: SLC26A5 NM_198999.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0160
• Publications: 1 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=-0.87).
• BP6: Variant 7-103376701-A-G is Benign according to our data. Variant chr7-103376701-A-G is described in ClinVar as Benign. ClinVar VariationId is 1269285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A5	NM_198999.3	c.2041+107T>C		intron_variant	Intron 19 of 19	ENST00000306312.8	NP_945350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A5	ENST00000306312.8	c.2041+107T>C		intron_variant	Intron 19 of 19	1	NM_198999.3	ENSP00000304783.3
SLC26A5	ENST00000393727.5	c.2047+107T>C		intron_variant	Intron 17 of 17	1		ENSP00000377328.1
SLC26A5	ENST00000393723.2	c.1951+107T>C		intron_variant	Intron 16 of 16	1		ENSP00000377324.1

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3114 AN: 152142 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.0716

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00700

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: 0.0000882

Gnomad OTH AF: 0.0167

GnomAD4 exome AF: 0.00207 AC: 1525 AN: 737188 Hom.: 48 AF XY: 0.00171 AC XY: 666 AN XY: 388956

African (AFR) AF: 0.0732 AC: 1224 AN: 16732

American (AMR) AF: 0.00367 AC: 102 AN: 27788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19026

East Asian (EAS) AF: 0.00 AC: 0 AN: 31742

South Asian (SAS) AF: 0.000139 AC: 8 AN: 57438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45968

Middle Eastern (MID) AF: 0.00331 AC: 10 AN: 3018

European-Non Finnish (NFE) AF: 0.0000380 AC: 19 AN: 500644

Other (OTH) AF: 0.00465 AC: 162 AN: 34832

GnomAD4 genome AF: 0.0205 AC: 3120 AN: 152260 Hom.: 102 Cov.: 32 AF XY: 0.0200 AC XY: 1491 AN XY: 74456

African (AFR) AF: 0.0716 AC: 2972 AN: 41526

American (AMR) AF: 0.00699 AC: 107 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68012

Other (OTH) AF: 0.0166 AC: 35 AN: 2112

Alfa AF: 0.0166 Hom.: 9

Bravo AF: 0.0230

Asia WGS AF: 0.00290 AC: 10 AN: 3458

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

- -

Apr 12, 2019

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	-0.87
CADD	Benign	2.2
DANN	Benign	0.72
PhyloP100		-0.016
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: rs72655393; hg19: chr7-103017148;