11-20601059-A-G

Variant names:

• chr11-20601059-A-G
• rs72944437
• NM_004211.5:c.4-70A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004211.5(SLC6A5):​c.4-70A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,479,216 control chromosomes in the GnomAD database, including 8,076 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1025 hom., cov: 33)
  • Exomes 𝑓: 0.099 (7051 hom.)
• Consequence: SLC6A5 NM_004211.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.18
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 11-20601059-A-G is Benign according to our data. Variant chr11-20601059-A-G is described in ClinVar as Benign. ClinVar VariationId is 1297945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A5	NM_004211.5	c.4-70A>G		intron_variant	Intron 1 of 15	ENST00000525748.6	NP_004202.4
SLC6A5	NM_001318369.2	c.-560-70A>G		intron_variant	Intron 1 of 14		NP_001305298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A5	ENST00000525748.6	c.4-70A>G		intron_variant	Intron 1 of 15	1	NM_004211.5	ENSP00000434364.2
SLC6A5	ENST00000298923.11	n.4-70A>G		intron_variant	Intron 1 of 14	1		ENSP00000298923.7

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16849 AN: 152154 Hom.: 1023 Cov.: 33

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0875

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.00693

Gnomad SAS AF: 0.0641

Gnomad FIN AF: 0.0511

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0957

GnomAD4 exome AF: 0.0991 AC: 131442 AN: 1326944 Hom.: 7051 AF XY: 0.0982 AC XY: 64473 AN XY: 656478

African (AFR) AF: 0.168 AC: 4916 AN: 29276

American (AMR) AF: 0.0686 AC: 2001 AN: 29152

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 3501 AN: 23434

East Asian (EAS) AF: 0.00215 AC: 77 AN: 35742

South Asian (SAS) AF: 0.0595 AC: 4410 AN: 74072

European-Finnish (FIN) AF: 0.0576 AC: 1961 AN: 34056

Middle Eastern (MID) AF: 0.0976 AC: 534 AN: 5474

European-Non Finnish (NFE) AF: 0.104 AC: 108314 AN: 1040042

Other (OTH) AF: 0.103 AC: 5728 AN: 55696

GnomAD4 genome AF: 0.111 AC: 16857 AN: 152272 Hom.: 1025 Cov.: 33 AF XY: 0.106 AC XY: 7871 AN XY: 74462

African (AFR) AF: 0.164 AC: 6796 AN: 41540

American (AMR) AF: 0.0873 AC: 1336 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 480 AN: 3472

East Asian (EAS) AF: 0.00694 AC: 36 AN: 5186

South Asian (SAS) AF: 0.0635 AC: 307 AN: 4834

European-Finnish (FIN) AF: 0.0511 AC: 543 AN: 10616

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7049 AN: 68006

Other (OTH) AF: 0.0947 AC: 200 AN: 2112

Alfa AF: 0.102 Hom.: 294

Bravo AF: 0.115

Asia WGS AF: 0.0530 AC: 189 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 17, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.015
DANN	Benign	0.55
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs72944437; hg19: chr11-20622605;