12-100380677-C-A

Variant names:

• chr12-100380677-C-A
• rs148710845
• NM_139319.3:c.102-24C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_139319.3(SLC17A8):​c.102-24C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00518 in 1,612,640 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0053 (27 hom.)
• Consequence: SLC17A8 NM_139319.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.184
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 12-100380677-C-A is Benign according to our data. Variant chr12-100380677-C-A is described in ClinVar as Benign. ClinVar VariationId is 1265235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 565 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.102-24C>A		intron	N/A	NP_647480.1	Q8NDX2-1
	SLC17A8	NM_001145288.2		c.102-24C>A		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.102-24C>A		intron	N/A	ENSP00000316909.4	Q8NDX2-1
	SLC17A8	ENST00000392989.3	TSL:1	c.102-24C>A		intron	N/A	ENSP00000376715.3	Q8NDX2-2
	SLC17A8	ENST00000874772.1		c.102-24C>A		intron	N/A	ENSP00000544831.1

Frequencies

GnomAD3 genomes AF: 0.00374 AC: 566 AN: 151162 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00238

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00222

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00653

Gnomad OTH AF: 0.00145

GnomAD2 exomes AF: 0.00372 AC: 925 AN: 248486 AF XY: 0.00355

Gnomad AFR exome AF: 0.000902

Gnomad AMR exome AF: 0.000984

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00305

Gnomad NFE exome AF: 0.00659

Gnomad OTH exome AF: 0.00329

GnomAD4 exome AF: 0.00533 AC: 7782 AN: 1461364 Hom.: 27 Cov.: 31 AF XY: 0.00526 AC XY: 3826 AN XY: 727010

African (AFR) AF: 0.000598 AC: 20 AN: 33466

American (AMR) AF: 0.000917 AC: 41 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 47 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00118 AC: 102 AN: 86216

European-Finnish (FIN) AF: 0.00316 AC: 169 AN: 53410

Middle Eastern (MID) AF: 0.00493 AC: 28 AN: 5680

European-Non Finnish (NFE) AF: 0.00645 AC: 7171 AN: 1111716

Other (OTH) AF: 0.00338 AC: 204 AN: 60360

GnomAD4 genome AF: 0.00373 AC: 565 AN: 151276 Hom.: 1 Cov.: 31 AF XY: 0.00389 AC XY: 287 AN XY: 73858

African (AFR) AF: 0.00112 AC: 46 AN: 41202

American (AMR) AF: 0.00237 AC: 36 AN: 15162

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4786

European-Finnish (FIN) AF: 0.00222 AC: 23 AN: 10360

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00653 AC: 443 AN: 67850

Other (OTH) AF: 0.00143 AC: 3 AN: 2096

Alfa AF: 0.00499 Hom.: 0

Bravo AF: 0.00349

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Benign	0.75
PhyloP100		0.18
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: rs148710845; hg19: chr12-100774455;