rs11568546

chr12-100380935-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_139319.3(SLC17A8):c.336T>C(p.Asp112=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,614,114 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0032 (11 hom.)
• Consequence: SLC17A8 NM_139319.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.596

Genes affected

SLC17A8 (HGNC:20151): (solute carrier family 17 member 8) This gene encodes a vesicular glutamate transporter. The encoded protein transports the neurotransmitter glutamate into synaptic vesicles before it is released into the synaptic cleft. Mutations in this gene are the cause of autosomal-dominant nonsyndromic type 25 deafness. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 12-100380935-T-C is Benign according to our data. Variant chr12-100380935-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 47883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-100380935-T-C is described in Lovd as [Likely_benign]. Variant chr12-100380935-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.596 with no splicing effect.
• BS2: High AC in GnomAd at 398 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC17A8	NM_139319.3	c.336T>C	p.Asp112=	synonymous_variant	2/12	ENST00000323346.10
SLC17A8	NM_001145288.2	c.336T>C	p.Asp112=	synonymous_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC17A8	ENST00000323346.10	c.336T>C	p.Asp112=	synonymous_variant	2/12	1	NM_139319.3	P1
SLC17A8	ENST00000392989.3	c.336T>C	p.Asp112=	synonymous_variant	2/11	1

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 398 AN: 152152 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00401

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00275 AC: 692 AN: 251426 Hom.: 1 AF XY: 0.00275 AC XY: 374 AN XY: 135886

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00461

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00315 AC: 4605 AN: 1461844 Hom.: 11 Cov.: 31 AF XY: 0.00310 AC XY: 2258 AN XY: 727226

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00161

Gnomad4 FIN exome AF: 0.00150

Gnomad4 NFE exome AF: 0.00360

Gnomad4 OTH exome AF: 0.00325

GnomAD4 genome AF: 0.00261 AC: 397 AN: 152270 Hom.: 1 Cov.: 31 AF XY: 0.00228 AC XY: 170 AN XY: 74456

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00401

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00340 Hom.: 1

Bravo AF: 0.00266

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00539

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Asp112Asp in Exon 02 of SLC17A8: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 0.4% (28/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs11568546). -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 03, 2019	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	SLC17A8: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 07, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2021	- -

Autosomal dominant nonsyndromic hearing loss 25 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	2.4
Dann	Benign	0.61

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: rs11568546; hg19: chr12-100774713;