11-20601467-C-G

Variant names:

• chr11-20601467-C-G
• rs61736605
• NM_004211.5:c.342C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004211.5(SLC6A5):​c.342C>G​(p.Pro114Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00987 in 1,611,348 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (6 hom., cov: 35)
  • Exomes 𝑓: 0.010 (94 hom.)
• Consequence: SLC6A5 NM_004211.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.07
• Publications: 1 publications found

Genes affected

SLC6A5 (HGNC:11051): (solute carrier family 6 member 5) This gene encodes a sodium- and chloride-dependent glycine neurotransmitter transporter. This integral membrane glycoprotein is responsible for the clearance of extracellular glycine during glycine-mediated neurotransmission. This protein is found in glycinergic axons and maintains a high presynaptic pool of neurotransmitter at glycinergic synapses. Mutations in this gene cause hyperekplexia; a heterogenous neurological disorder characterized by exaggerated startle responses and neonatal apnea. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

SLC6A5 Gene-Disease associations (from GenCC):

• hyperekplexia 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 11-20601467-C-G is Benign according to our data. Variant chr11-20601467-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 304004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00748 (1139/152342) while in subpopulation NFE AF = 0.0126 (857/68030). AF 95% confidence interval is 0.0119. There are 6 homozygotes in GnomAd4. There are 504 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004211.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A5	NM_004211.5	MANE Select	c.342C>G	p.Pro114Pro	synonymous	Exon 2 of 16	NP_004202.4
	SLC6A5	NM_001318369.2		c.-222C>G		5_prime_UTR	Exon 2 of 15	NP_001305298.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A5	ENST00000525748.6	TSL:1 MANE Select	c.342C>G	p.Pro114Pro	synonymous	Exon 2 of 16	ENSP00000434364.2
	SLC6A5	ENST00000298923.11	TSL:1	n.342C>G		non_coding_transcript_exon	Exon 2 of 15	ENSP00000298923.7

Frequencies

GnomAD3 genomes AF: 0.00748 AC: 1139 AN: 152224 Hom.: 6 Cov.: 35

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00405

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00692 AC: 1669 AN: 241166 AF XY: 0.00689

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00225

Gnomad ASJ exome AF: 0.00153

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0101

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.00560

GnomAD4 exome AF: 0.0101 AC: 14760 AN: 1459006 Hom.: 94 Cov.: 70 AF XY: 0.00987 AC XY: 7161 AN XY: 725654

African (AFR) AF: 0.00176 AC: 59 AN: 33446

American (AMR) AF: 0.00253 AC: 112 AN: 44288

Ashkenazi Jewish (ASJ) AF: 0.00177 AC: 46 AN: 26026

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39588

South Asian (SAS) AF: 0.00160 AC: 137 AN: 85820

European-Finnish (FIN) AF: 0.00969 AC: 514 AN: 53050

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5762

European-Non Finnish (NFE) AF: 0.0121 AC: 13405 AN: 1110812

Other (OTH) AF: 0.00784 AC: 472 AN: 60214

GnomAD4 genome AF: 0.00748 AC: 1139 AN: 152342 Hom.: 6 Cov.: 35 AF XY: 0.00677 AC XY: 504 AN XY: 74496

African (AFR) AF: 0.00221 AC: 92 AN: 41586

American (AMR) AF: 0.00405 AC: 62 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4834

European-Finnish (FIN) AF: 0.0102 AC: 108 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0126 AC: 857 AN: 68030

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00694 Hom.: 0

Bravo AF: 0.00647

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hyperekplexia 3 (2)
-	-	2	not provided (2)
-	-	1	Hyperekplexia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.23
DANN	Benign	0.66
PhyloP100		-2.1
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: rs61736605; hg19: chr11-20623013;