rs77707755

Variant names:

• chr12-100380969-T-C
• rs77707755
• NM_139319.3:c.354+16T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_139319.3(SLC17A8):​c.354+16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00399 in 1,613,734 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0040 (14 hom.)
• Consequence: SLC17A8 NM_139319.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.594
• Publications: 0 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-100380969-T-C is Benign according to our data. Variant chr12-100380969-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 560 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.354+16T>C		intron	N/A	NP_647480.1	Q8NDX2-1
	SLC17A8	NM_001145288.2		c.354+16T>C		intron	N/A	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.354+16T>C		intron	N/A	ENSP00000316909.4	Q8NDX2-1
	SLC17A8	ENST00000392989.3	TSL:1	c.354+16T>C		intron	N/A	ENSP00000376715.3	Q8NDX2-2
	SLC17A8	ENST00000874772.1		c.354+16T>C		intron	N/A	ENSP00000544831.1

Frequencies

GnomAD3 genomes AF: 0.00367 AC: 559 AN: 152170 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00410

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00306 AC: 767 AN: 251028 AF XY: 0.00301

Gnomad AFR exome AF: 0.00468

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00305

Gnomad NFE exome AF: 0.00427

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00402 AC: 5877 AN: 1461446 Hom.: 14 Cov.: 31 AF XY: 0.00388 AC XY: 2818 AN XY: 727060

African (AFR) AF: 0.00571 AC: 191 AN: 33466

American (AMR) AF: 0.00208 AC: 93 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00199 AC: 52 AN: 26136

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

South Asian (SAS) AF: 0.00119 AC: 103 AN: 86232

European-Finnish (FIN) AF: 0.00303 AC: 162 AN: 53420

Middle Eastern (MID) AF: 0.00515 AC: 28 AN: 5442

European-Non Finnish (NFE) AF: 0.00452 AC: 5031 AN: 1111976

Other (OTH) AF: 0.00360 AC: 217 AN: 60354

GnomAD4 genome AF: 0.00368 AC: 560 AN: 152288 Hom.: 1 Cov.: 31 AF XY: 0.00342 AC XY: 255 AN XY: 74464

African (AFR) AF: 0.00433 AC: 180 AN: 41550

American (AMR) AF: 0.00183 AC: 28 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

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

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00410 AC: 279 AN: 68022

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00309 Hom.: 0

Bravo AF: 0.00411

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.014
DANN	Benign	0.36
PhyloP100		-0.59
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: rs77707755; hg19: chr12-100774747;