chr7-103376685-CAGA-C

Variant names:

• chr7-103376685-CAGA-C
• rs66928926
• NM_198999.3:c.2041+120_2041+122delTCT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_198999.3(SLC26A5):​c.2041+120_2041+122delTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0586 in 779,124 control chromosomes in the GnomAD database, including 2,881 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1609 hom., cov: 30)
  • Exomes 𝑓: 0.047 (1272 hom.)
• Consequence: SLC26A5 NM_198999.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.539
• Publications: 2 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 -10 ACMG points.

• BP6: Variant 7-103376685-CAGA-C is Benign according to our data. Variant chr7-103376685-CAGA-C is described in ClinVar as Benign. ClinVar VariationId is 1287837.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A5	NM_198999.3	MANE Select	c.2041+120_2041+122delTCT		intron	N/A	NP_945350.1
	SLC26A5	NM_001167962.2		c.1945+120_1945+122delTCT		intron	N/A	NP_001161434.1
	SLC26A5	NM_206883.3		c.2041+120_2041+122delTCT		intron	N/A	NP_996766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A5	ENST00000306312.8	TSL:1 MANE Select	c.2041+120_2041+122delTCT		intron	N/A	ENSP00000304783.3
	SLC26A5	ENST00000393727.5	TSL:1	c.2047+120_2047+122delTCT		intron	N/A	ENSP00000377328.1
	SLC26A5	ENST00000393723.2	TSL:1	c.1951+120_1951+122delTCT		intron	N/A	ENSP00000377324.1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16188 AN: 151858 Hom.: 1610 Cov.: 30

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0504

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.0935

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0424

Gnomad OTH AF: 0.0852

GnomAD4 exome AF: 0.0470 AC: 29454 AN: 627148 Hom.: 1272 AF XY: 0.0440 AC XY: 14661 AN XY: 332872

African (AFR) AF: 0.285 AC: 4244 AN: 14866

American (AMR) AF: 0.0396 AC: 885 AN: 22340

Ashkenazi Jewish (ASJ) AF: 0.0175 AC: 300 AN: 17174

East Asian (EAS) AF: 0.0000661 AC: 2 AN: 30252

South Asian (SAS) AF: 0.00851 AC: 424 AN: 49830

European-Finnish (FIN) AF: 0.0931 AC: 3926 AN: 42186

Middle Eastern (MID) AF: 0.0178 AC: 43 AN: 2418

European-Non Finnish (NFE) AF: 0.0432 AC: 18008 AN: 417180

Other (OTH) AF: 0.0525 AC: 1622 AN: 30902

GnomAD4 genome AF: 0.107 AC: 16208 AN: 151976 Hom.: 1609 Cov.: 30 AF XY: 0.105 AC XY: 7823 AN XY: 74286

African (AFR) AF: 0.273 AC: 11297 AN: 41360

American (AMR) AF: 0.0504 AC: 770 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4820

European-Finnish (FIN) AF: 0.0935 AC: 987 AN: 10558

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0424 AC: 2880 AN: 67988

Other (OTH) AF: 0.0843 AC: 178 AN: 2112

Alfa AF: 0.0823 Hom.: 125

Bravo AF: 0.112

Asia WGS AF: 0.0180 AC: 62 AN: 3464

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.54
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: rs66928926; hg19: chr7-103017132;