11-22341664-A-G

Position:

• chr11-22341664-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_020346.3(SLC17A6):​c.223A>G​(p.Ile75Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SLC17A6 NM_020346.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.18

Genes affected

SLC17A6 (HGNC:16703): (solute carrier family 17 member 6) Predicted to enable L-glutamate transmembrane transporter activity and neurotransmitter transmembrane transporter activity. Involved in neurotransmitter loading into synaptic vesicle. Predicted to be located in synaptic vesicle. Predicted to be active in excitatory synapse. Predicted to be integral component of synaptic vesicle membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18953785).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC17A6	NM_020346.3	c.223A>G	p.Ile75Val	missense_variant	2/12	ENST00000263160.4	NP_065079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC17A6	ENST00000263160.4	c.223A>G	p.Ile75Val	missense_variant	2/12	1	NM_020346.3	ENSP00000263160.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2022

The c.223A>G (p.I75V) alteration is located in exon 2 (coding exon 2) of the SLC17A6 gene. This alteration results from a A to G substitution at nucleotide position 223, causing the isoleucine (I) at amino acid position 75 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.052
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.050
Sift	Benign	0.19	T
Sift4G	Benign	0.38	T
Polyphen		0.0010	B
Vest4		0.33
MutPred		0.30		Gain of sheet (P = 0.0827);
MVP		0.11
MPC		0.29
ClinPred		0.70	D
GERP RS		4.9
Varity_R		0.16
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-22363210;