Genetic Variant NM_198999.3:c.-53-2A>G (chr7-103421569-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBS1BS2

The NM_198999.3(SLC26A5):c.-53-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,583,898 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0074 ( 8 hom., cov: 32)

Exomes 𝑓: 0.012 ( 102 hom. )

Consequence

SLC26A5
NM_198999.3 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:6

Conservation

PhyloP100: 0.747

Publications

8 publications found

Variant links:

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

SLC26A5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.9, offset of 10, new splice context is: tttcccctggtgacactcAGgaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

BP6

Variant 7-103421569-T-C is Benign according to our data. Variant chr7-103421569-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 5289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00738 (1124/152240) while in subpopulation NFE AF = 0.0118 (801/68008). AF 95% confidence interval is 0.0111. There are 8 homozygotes in GnomAd4. There are 527 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SLC26A5	NM_198999.3	MANE Select	c.-53-2A>G	splice_acceptor intron	N/A	NP_945350.1
SLC26A5	NM_001167962.2		c.-53-2A>G	splice_acceptor intron	N/A	NP_001161434.1
SLC26A5	NM_206883.3		c.-53-2A>G	splice_acceptor intron	N/A	NP_996766.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SLC26A5	ENST00000306312.8	TSL:1 MANE Select	c.-53-2A>G	splice_acceptor intron	N/A	ENSP00000304783.3
SLC26A5	ENST00000393730.5	TSL:1	c.-53-2A>G	splice_acceptor intron	N/A	ENSP00000377331.1
SLC26A5	ENST00000339444.10	TSL:1	c.-53-2A>G	splice_acceptor intron	N/A	ENSP00000342396.6

Frequencies

GnomAD3 genomes

AF:

0.00739

AC:

1124

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00205

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00675

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.00782

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.00526

GnomAD4 exome

AF:

0.0115

AC:

16496

AN:

1431658

Hom.:

102

Cov.:

AF XY:

0.0114

AC XY:

8117

AN XY:

714134

show subpopulations

African (AFR)

AF:

0.00201

AC:

AN:

32880

American (AMR)

AF:

0.00421

AC:

188

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.00362

AC:

AN:

25980

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39542

South Asian (SAS)

AF:

0.00859

AC:

737

AN:

85758

European-Finnish (FIN)

AF:

0.00987

AC:

500

AN:

50672

Middle Eastern (MID)

AF:

0.000529

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

0.0131

AC:

14207

AN:

1087124

Other (OTH)

AF:

0.0118

AC:

700

AN:

59416

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

835

1670

2504

3339

4174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

538

1076

1614

2152

2690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00738

AC:

1124

AN:

152240

Hom.:

Cov.:

AF XY:

0.00708

AC XY:

527

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00205

AC:

AN:

41558

American (AMR)

AF:

0.00674

AC:

103

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00477

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00782

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0118

AC:

801

AN:

68008

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

112

169

225

281

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00933

Hom.:

Bravo

AF:

0.00721

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 61

Uncertain:1Benign:2

Sep 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 02, 2014

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

not specified

Benign:2

Feb 02, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

May 05, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC26A5: BS1, BS2

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Pathogenic

(source)

DANN

Benign

0.69

PhyloP100

0.75

PromoterAI

0.016

Neutral

(source)

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.76

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.85

Position offset: -12

DS_AL_spliceai

0.99

Position offset: -2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over