chr7-103391608-T-C

Position:

• chr7-103391608-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198999.3(SLC26A5):​c.1233+14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,604,174 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00099 (3 hom., cov: 32)
  • Exomes 𝑓: 0.000087 (3 hom.)
• Consequence: SLC26A5 NM_198999.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.01

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-103391608-T-C is Benign according to our data. Variant chr7-103391608-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 48335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103391608-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000991 (151/152336) while in subpopulation AMR AF= 0.00967 (148/15306). AF 95% confidence interval is 0.0084. There are 3 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A5	NM_198999.3	c.1233+14A>G		intron_variant		ENST00000306312.8	NP_945350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A5	ENST00000306312.8	c.1233+14A>G		intron_variant		1	NM_198999.3	ENSP00000304783.3
SLC26A5	ENST00000393727.5	c.1233+14A>G		intron_variant		1		ENSP00000377328.1
SLC26A5	ENST00000393723.2	c.1233+14A>G		intron_variant		1		ENSP00000377324.1

Frequencies

GnomAD3 genomes AF: 0.000985 AC: 150 AN: 152218 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00962

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: 0.00

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000338 AC: 85 AN: 251190 Hom.: 2 AF XY: 0.000280 AC XY: 38 AN XY: 135760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000875 AC: 127 AN: 1451838 Hom.: 3 Cov.: 28 AF XY: 0.0000816 AC XY: 59 AN XY: 723038

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000991 AC: 151 AN: 152336 Hom.: 3 Cov.: 32 AF XY: 0.00140 AC XY: 104 AN XY: 74492

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00967

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.000808

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 28, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 25, 2013

1233+14A>G in intron 11: This variant is not expected to have clinical significa nce because it is not located within the splice consensus sequence and it has be en identified in 2% (2/120) of Colombian chromosomes from the 1000 Genomes Seque ncing Project (www.1000genomes.org; dbSNP rs191459658) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.29
DANN	Benign	0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs191459658; hg19: chr7-103032055;