rs62636580

Variant names:

• chr5-151822799-G-A
• rs62636580
• NM_000171.4:c.1224C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000171.4(GLRA1):​c.1224C>T​(p.Phe408Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0044 in 1,614,090 control chromosomes in the GnomAD database, including 272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (137 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (135 hom.)
• Consequence: GLRA1 NM_000171.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.52
• Publications: 2 publications found

Genes affected

GLRA1 (HGNC:4326): (glycine receptor alpha 1) The protein encoded by this gene is a subunit of a pentameric inhibitory glycine receptor, which mediates postsynaptic inhibition in the central nervous system. Defects in this gene are a cause of startle disease (STHE), also known as hereditary hyperekplexia or congenital stiff-person syndrome. Multiple transcript variants encoding different isoforms have been found. [provided by RefSeq, Dec 2015]

GLRA1 Gene-Disease associations (from GenCC):

• hyperekplexia 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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=-0.54).
• BP6: Variant 5-151822799-G-A is Benign according to our data. Variant chr5-151822799-G-A is described in ClinVar as Benign. ClinVar VariationId is 352306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0787 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000171.4. 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
	GLRA1	NM_000171.4	MANE Select	c.1224C>T	p.Phe408Phe	synonymous	Exon 9 of 9	NP_000162.2	P23415-2
	GLRA1	NM_001146040.2		c.1248C>T	p.Phe416Phe	synonymous	Exon 9 of 9	NP_001139512.1	P23415-1
	GLRA1	NM_001292000.2		c.975C>T	p.Phe325Phe	synonymous	Exon 8 of 8	NP_001278929.1	Q14C71

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA1	ENST00000274576.9	TSL:1 MANE Select	c.1224C>T	p.Phe408Phe	synonymous	Exon 9 of 9	ENSP00000274576.5	P23415-2
	GLRA1	ENST00000455880.2	TSL:1	c.1248C>T	p.Phe416Phe	synonymous	Exon 9 of 9	ENSP00000411593.2	P23415-1
	GLRA1	ENST00000462581.6	TSL:1	n.*982C>T		non_coding_transcript_exon	Exon 8 of 8	ENSP00000430595.1	E5RJ70

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3536 AN: 152152 Hom.: 135 Cov.: 31

Gnomad AFR AF: 0.0808

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00590 AC: 1484 AN: 251412 AF XY: 0.00411

Gnomad AFR exome AF: 0.0817

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00243 AC: 3548 AN: 1461820 Hom.: 135 Cov.: 31 AF XY: 0.00209 AC XY: 1519 AN XY: 727218

African (AFR) AF: 0.0855 AC: 2861 AN: 33470

American (AMR) AF: 0.00367 AC: 164 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.000138 AC: 153 AN: 1111956

Other (OTH) AF: 0.00530 AC: 320 AN: 60394

GnomAD4 genome AF: 0.0233 AC: 3554 AN: 152270 Hom.: 137 Cov.: 31 AF XY: 0.0222 AC XY: 1655 AN XY: 74458

African (AFR) AF: 0.0810 AC: 3364 AN: 41548

American (AMR) AF: 0.00896 AC: 137 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68030

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.0135 Hom.: 48

Bravo AF: 0.0269

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary hyperekplexia (1)
-	-	1	Hyperekplexia 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	10
DANN	Benign	0.73
PhyloP100		3.5
Mutation Taster		=97/3	polymorphism (auto)

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: rs62636580; hg19: chr5-151202360;