7-103420728-A-ATC

Variant names:

• chr7-103420728-A-ATC
• rs112791865
• NM_198999.3:c.292+8_292+9dupGA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_198999.3(SLC26A5):​c.292+8_292+9dupGA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000562 in 1,613,984 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (4 hom.)
• Consequence: SLC26A5 NM_198999.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0990
• Publications: 0 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 -16 ACMG points.

• BP6: Variant 7-103420728-A-ATC is Benign according to our data. Variant chr7-103420728-A-ATC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00278 (424/152316) while in subpopulation AFR AF = 0.00981 (408/41572). AF 95% confidence interval is 0.00903. There are 4 homozygotes in GnomAd4. There are 194 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A5	NM_198999.3	MANE Select	c.292+8_292+9dupGA		intron	N/A	NP_945350.1
	SLC26A5	NM_001167962.2		c.292+8_292+9dupGA		intron	N/A	NP_001161434.1
	SLC26A5	NM_206883.3		c.292+8_292+9dupGA		intron	N/A	NP_996766.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A5	ENST00000306312.8	TSL:1 MANE Select	c.292+9_292+10insGA		intron	N/A	ENSP00000304783.3
	SLC26A5	ENST00000393727.5	TSL:1	c.292+9_292+10insGA		intron	N/A	ENSP00000377328.1
	SLC26A5	ENST00000393723.2	TSL:1	c.292+9_292+10insGA		intron	N/A	ENSP00000377324.1

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 405 AN: 152198 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00938

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000710 AC: 178 AN: 250802 AF XY: 0.000457

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000330 AC: 483 AN: 1461668 Hom.: 4 Cov.: 31 AF XY: 0.000285 AC XY: 207 AN XY: 727138

African (AFR) AF: 0.0111 AC: 373 AN: 33472

American (AMR) AF: 0.000224 AC: 10 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111948

Other (OTH) AF: 0.00142 AC: 86 AN: 60390

GnomAD4 genome AF: 0.00278 AC: 424 AN: 152316 Hom.: 4 Cov.: 32 AF XY: 0.00260 AC XY: 194 AN XY: 74492

African (AFR) AF: 0.00981 AC: 408 AN: 41572

American (AMR) AF: 0.000523 AC: 8 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00116 Hom.: 1

Bravo AF: 0.00313

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.099
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs112791865; hg19: chr7-103061175;