chr11-35418965-A-C

Variant names:

• chr11-35418965-A-C
• rs1855696404
• NM_004171.4:c.2T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PVS1_Supporting PM2 BP6_Moderate

The NM_004171.4(SLC1A2):​c.2T>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000706 in 1,415,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SLC1A2 NM_004171.4 start_lost
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.35
• Publications: 0 publications found

Genes affected

SLC1A2 (HGNC:10940): (solute carrier family 1 member 2) This gene encodes a member of a family of solute transporter proteins. The membrane-bound protein is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors. Improper regulation of this gene is thought to be associated with several neurological disorders. Alternatively spliced transcript variants of this gene have been identified. [provided by RefSeq, Jun 2017]

SLC1A2-AS2 (HGNC:40535): (SLC1A2 antisense RNA 2)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 10 codons. Genomic position: 35317506. Lost 0.016 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 11-35418965-A-C is Benign according to our data. Variant chr11-35418965-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1535497.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004171.4. 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
	SLC1A2	NM_004171.4	MANE Select	c.2T>G	p.Met1?	start_lost	Exon 1 of 11	NP_004162.2
	SLC1A2	NM_001439343.1		c.2T>G	p.Met1?	start_lost	Exon 1 of 10	NP_001426272.1
	SLC1A2	NM_001439342.1		c.5+971T>G		intron	N/A	NP_001426271.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC1A2	ENST00000278379.9	TSL:1 MANE Select	c.2T>G	p.Met1?	start_lost	Exon 1 of 11	ENSP00000278379.3	P43004-1
	SLC1A2	ENST00000395750.6	TSL:1	c.5+971T>G		intron	N/A	ENSP00000379099.2	A0A2U3TZS7
	SLC1A2	ENST00000901507.1		c.2T>G	p.Met1?	start_lost	Exon 1 of 11	ENSP00000571566.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1415634 Hom.: 0 Cov.: 30 AF XY: 0.00000143 AC XY: 1 AN XY: 699708

African (AFR) AF: 0.00 AC: 0 AN: 32456

American (AMR) AF: 0.00 AC: 0 AN: 38922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25296

East Asian (EAS) AF: 0.00 AC: 0 AN: 37286

South Asian (SAS) AF: 0.00 AC: 0 AN: 80458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1086824

Other (OTH) AF: 0.00 AC: 0 AN: 58610

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.91	T
PhyloP100		3.3
PROVEAN	Benign	0.23	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.010	D
Polyphen		0.68	P
Vest4		0.87
MutPred		0.99		Gain of MoRF binding (P = 6e-04)
MVP		0.65
ClinPred		0.92	D
GERP RS		4.3
PromoterAI		-0.26	Neutral
Varity_R		0.88
gMVP		0.84
Mutation Taster		=85/115	disease causing

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: rs1855696404; hg19: chr11-35440512;