NM_198999.3:c.1312-44T>C

Variant names:

• chr7-103389468-A-G
• rs62482415
• NM_198999.3:c.1312-44T>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.1312-44T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,439,138 control chromosomes in the GnomAD database, including 15,869 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1569 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14300 hom.)
• Consequence: SLC26A5 NM_198999.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.975
• Publications: 4 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=-0.65).
• BP6: Variant 7-103389468-A-G is Benign according to our data. Variant chr7-103389468-A-G is described in ClinVar as Benign. ClinVar VariationId is 1237911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A5	NM_198999.3	c.1312-44T>C		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.1312-44T>C		intron_variant	Intron 12 of 19	1	NM_198999.3	ENSP00000304783.3
SLC26A5	ENST00000393727.5	c.1312-44T>C		intron_variant	Intron 10 of 17	1		ENSP00000377328.1
SLC26A5	ENST00000393723.2	c.1312-354T>C		intron_variant	Intron 10 of 16	1		ENSP00000377324.1

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20838 AN: 151850 Hom.: 1565 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.0906

Gnomad EAS AF: 0.0677

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.121

GnomAD2 exomes AF: 0.151 AC: 37594 AN: 249428 AF XY: 0.152

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.0849

Gnomad EAS exome AF: 0.0629

Gnomad FIN exome AF: 0.225

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.145 AC: 186336 AN: 1287170 Hom.: 14300 Cov.: 18 AF XY: 0.146 AC XY: 94505 AN XY: 649486

African (AFR) AF: 0.115 AC: 3464 AN: 30116

American (AMR) AF: 0.187 AC: 8283 AN: 44318

Ashkenazi Jewish (ASJ) AF: 0.0855 AC: 2137 AN: 25002

East Asian (EAS) AF: 0.0754 AC: 2935 AN: 38912

South Asian (SAS) AF: 0.183 AC: 15139 AN: 82616

European-Finnish (FIN) AF: 0.221 AC: 11762 AN: 53150

Middle Eastern (MID) AF: 0.0860 AC: 469 AN: 5456

European-Non Finnish (NFE) AF: 0.141 AC: 134768 AN: 953064

Other (OTH) AF: 0.135 AC: 7379 AN: 54536

GnomAD4 genome AF: 0.137 AC: 20854 AN: 151968 Hom.: 1569 Cov.: 32 AF XY: 0.142 AC XY: 10514 AN XY: 74256

African (AFR) AF: 0.115 AC: 4784 AN: 41446

American (AMR) AF: 0.155 AC: 2373 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0906 AC: 314 AN: 3466

East Asian (EAS) AF: 0.0679 AC: 350 AN: 5156

South Asian (SAS) AF: 0.167 AC: 799 AN: 4796

European-Finnish (FIN) AF: 0.229 AC: 2418 AN: 10554

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9452 AN: 67964

Other (OTH) AF: 0.121 AC: 255 AN: 2114

Alfa AF: 0.130 Hom.: 401

Bravo AF: 0.129

Asia WGS AF: 0.112 AC: 389 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 21, 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	-0.65
CADD	Benign	12
DANN	Benign	0.89
PhyloP100		0.97
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs62482415; hg19: chr7-103029915; COSMIC: COSV59707468;