rs11568546

Variant names:

• chr12-100380935-T-C
• rs11568546
• NM_139319.3:c.336T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_139319.3(SLC17A8):​c.336T>C​(p.Asp112Asp) 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:8
• Conservation: PhyloP100: 0.596
• Publications: 3 publications found

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]

SLC17A8 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss 25

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 47883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.596 with no splicing effect.
• BS2: High AC in GnomAd4 at 397 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139319.3. 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
	SLC17A8	NM_139319.3	MANE Select	c.336T>C	p.Asp112Asp	synonymous	Exon 2 of 12	NP_647480.1	Q8NDX2-1
	SLC17A8	NM_001145288.2		c.336T>C	p.Asp112Asp	synonymous	Exon 2 of 11	NP_001138760.1	Q8NDX2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC17A8	ENST00000323346.10	TSL:1 MANE Select	c.336T>C	p.Asp112Asp	synonymous	Exon 2 of 12	ENSP00000316909.4	Q8NDX2-1
	SLC17A8	ENST00000392989.3	TSL:1	c.336T>C	p.Asp112Asp	synonymous	Exon 2 of 11	ENSP00000376715.3	Q8NDX2-2
	SLC17A8	ENST00000874772.1		c.336T>C	p.Asp112Asp	synonymous	Exon 3 of 13	ENSP00000544831.1

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

GnomAD2 exomes AF: 0.00275 AC: 692 AN: 251426 AF XY: 0.00275

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 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

African (AFR) AF: 0.000687 AC: 23 AN: 33480

American (AMR) AF: 0.00170 AC: 76 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 32 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00161 AC: 139 AN: 86252

European-Finnish (FIN) AF: 0.00150 AC: 80 AN: 53420

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5734

European-Non Finnish (NFE) AF: 0.00360 AC: 3998 AN: 1112002

Other (OTH) AF: 0.00325 AC: 196 AN: 60396

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

African (AFR) AF: 0.000794 AC: 33 AN: 41536

American (AMR) AF: 0.00190 AC: 29 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00401 AC: 273 AN: 68038

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00350 Hom.: 1

Bravo AF: 0.00266

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00539

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 25 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.4
DANN	Benign	0.61
PhyloP100		0.60
Mutation Taster		=100/0	polymorphism

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: rs11568546; hg19: chr12-100774713;