rs11568528

Variant names:

• chr12-100357445-G-A
• rs11568528
• NM_139319.3:c.54G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_139319.3(SLC17A8):​c.54G>A​(p.Lys18Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,613,994 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (21 hom.)
• Consequence: SLC17A8 NM_139319.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.601
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 12-100357445-G-A is Benign according to our data. Variant chr12-100357445-G-A is described in ClinVar as Benign. ClinVar VariationId is 47884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.601 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00899 (1369/152326) while in subpopulation AFR AF = 0.0314 (1304/41572). AF 95% confidence interval is 0.03. There are 17 homozygotes in GnomAd4. There are 661 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1369 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.54G>A	p.Lys18Lys	synonymous	Exon 1 of 12	NP_647480.1
	SLC17A8	NM_001145288.2		c.54G>A	p.Lys18Lys	synonymous	Exon 1 of 11	NP_001138760.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC17A8	ENST00000323346.10	TSL:1 MANE Select	c.54G>A	p.Lys18Lys	synonymous	Exon 1 of 12	ENSP00000316909.4
	SLC17A8	ENST00000392989.3	TSL:1	c.54G>A	p.Lys18Lys	synonymous	Exon 1 of 11	ENSP00000376715.3
	SLC17A8	ENST00000874772.1		c.54G>A	p.Lys18Lys	synonymous	Exon 2 of 13	ENSP00000544831.1

Frequencies

GnomAD3 genomes AF: 0.00900 AC: 1370 AN: 152208 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00245 AC: 617 AN: 251404 AF XY: 0.00175

Gnomad AFR exome AF: 0.0335

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000872 AC: 1274 AN: 1461668 Hom.: 21 Cov.: 29 AF XY: 0.000710 AC XY: 516 AN XY: 727156

African (AFR) AF: 0.0306 AC: 1024 AN: 33474

American (AMR) AF: 0.00208 AC: 93 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111816

Other (OTH) AF: 0.00192 AC: 116 AN: 60384

GnomAD4 genome AF: 0.00899 AC: 1369 AN: 152326 Hom.: 17 Cov.: 32 AF XY: 0.00887 AC XY: 661 AN XY: 74502

African (AFR) AF: 0.0314 AC: 1304 AN: 41572

American (AMR) AF: 0.00340 AC: 52 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00487 Hom.: 13

Bravo AF: 0.0110

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Autosomal dominant nonsyndromic hearing loss 25 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	5.5
DANN	Benign	0.61
PhyloP100		0.60
PromoterAI		-0.0014	Neutral
Mutation Taster		=98/2	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: rs11568528; hg19: chr12-100751223;