rs1952070

Variant names:

• chr14-66641352-A-G
• rs1952070
• NM_020806.5:c.65-39755A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020806.5(GPHN):​c.65-39755A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 152,082 control chromosomes in the GnomAD database, including 11,184 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (11184 hom., cov: 32)
• Consequence: GPHN NM_020806.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.698
• Publications: 3 publications found

Genes affected

GPHN (HGNC:15465): (gephyrin) This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperplexia and also lead to molybdenum cofactor deficiency. Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known. [provided by RefSeq, Jul 2008]

GPHN Gene-Disease associations (from GenCC):

• sulfite oxidase deficiency due to molybdenum cofactor deficiency type C

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.629 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020806.5. 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
	GPHN	NM_020806.5	MANE Select	c.65-39755A>G		intron	N/A	NP_065857.1
	GPHN	NM_001377514.1		c.65-39755A>G		intron	N/A	NP_001364443.1
	GPHN	NM_001377515.1		c.65-39755A>G		intron	N/A	NP_001364444.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPHN	ENST00000478722.6	TSL:1 MANE Select	c.65-39755A>G		intron	N/A	ENSP00000417901.1
	GPHN	ENST00000315266.9	TSL:1	c.65-39755A>G		intron	N/A	ENSP00000312771.5
	GPHN	ENST00000543237.5	TSL:2	c.65-39755A>G		intron	N/A	ENSP00000438404.1

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47168 AN: 151964 Hom.: 11168 Cov.: 32

Gnomad AFR AF: 0.635

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.469

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.296

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.311 AC: 47237 AN: 152082 Hom.: 11184 Cov.: 32 AF XY: 0.313 AC XY: 23295 AN XY: 74346

African (AFR) AF: 0.635 AC: 26348 AN: 41476

American (AMR) AF: 0.372 AC: 5674 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 781 AN: 3470

East Asian (EAS) AF: 0.469 AC: 2426 AN: 5170

South Asian (SAS) AF: 0.321 AC: 1546 AN: 4818

European-Finnish (FIN) AF: 0.140 AC: 1479 AN: 10592

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8176 AN: 67992

Other (OTH) AF: 0.294 AC: 618 AN: 2102

Alfa AF: 0.177 Hom.: 2033

Bravo AF: 0.344

Asia WGS AF: 0.368 AC: 1282 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.8
DANN	Benign	0.44
PhyloP100		-0.70
Mutation Taster		=100/0	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: rs1952070; hg19: chr14-67108070;