NM_000171.4:c.117G>C

Variant names:

• chr5-151892378-C-G
• rs149023945
• NM_000171.4:c.117G>C

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_000171.4(GLRA1):​c.117G>C​(p.Ser39Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,613,946 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S39S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (2 hom.)
• Consequence: GLRA1 NM_000171.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.44
• Publications: 1 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=-0.65).
• BP6: Variant 5-151892378-C-G is Benign according to our data. Variant chr5-151892378-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 352321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00166 (253/152228) while in subpopulation NFE AF = 0.00231 (157/68012). AF 95% confidence interval is 0.00201. There are 1 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

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.117G>C	p.Ser39Ser	synonymous	Exon 2 of 9	NP_000162.2	P23415-2
	GLRA1	NM_001146040.2		c.117G>C	p.Ser39Ser	synonymous	Exon 2 of 9	NP_001139512.1	P23415-1
	GLRA1	NM_001292000.2		c.-65-5590G>C		intron	N/A	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.117G>C	p.Ser39Ser	synonymous	Exon 2 of 9	ENSP00000274576.5	P23415-2
	GLRA1	ENST00000455880.2	TSL:1	c.117G>C	p.Ser39Ser	synonymous	Exon 2 of 9	ENSP00000411593.2	P23415-1
	GLRA1	ENST00000471351.2	TSL:1	n.400G>C		non_coding_transcript_exon	Exon 2 of 8

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 251 AN: 152110 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00148 AC: 373 AN: 251252 AF XY: 0.00162

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00444

Gnomad NFE exome AF: 0.00185

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00178 AC: 2601 AN: 1461718 Hom.: 2 Cov.: 31 AF XY: 0.00185 AC XY: 1344 AN XY: 727174

African (AFR) AF: 0.000119 AC: 4 AN: 33476

American (AMR) AF: 0.000313 AC: 14 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00139 AC: 120 AN: 86254

European-Finnish (FIN) AF: 0.00431 AC: 230 AN: 53412

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5764

European-Non Finnish (NFE) AF: 0.00190 AC: 2112 AN: 1111874

Other (OTH) AF: 0.00167 AC: 101 AN: 60388

GnomAD4 genome AF: 0.00166 AC: 253 AN: 152228 Hom.: 1 Cov.: 32 AF XY: 0.00161 AC XY: 120 AN XY: 74416

African (AFR) AF: 0.000409 AC: 17 AN: 41528

American (AMR) AF: 0.00118 AC: 18 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4826

European-Finnish (FIN) AF: 0.00424 AC: 45 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00231 AC: 157 AN: 68012

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00140 Hom.: 0

Bravo AF: 0.00117

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00196

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.68
DANN	Benign	0.62
PhyloP100		-4.4
Mutation Taster		=98/2	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: rs149023945; hg19: chr5-151271939;