NM_020806.5:c.65-1062A>G

Variant names:

• chr14-66680045-A-G
• rs17182817
• NM_020806.5:c.65-1062A>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.65-1062A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0586 in 152,332 control chromosomes in the GnomAD database, including 358 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 0.059 (358 hom., cov: 32)
• Consequence: GPHN NM_020806.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0350
• Publications: 0 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0819 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPHN	NM_020806.5	c.65-1062A>G		intron_variant	Intron 1 of 22	ENST00000478722.6	NP_065857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPHN	ENST00000478722.6	c.65-1062A>G		intron_variant	Intron 1 of 22	1	NM_020806.5	ENSP00000417901.1

Frequencies

GnomAD3 genomes AF: 0.0587 AC: 8928 AN: 152214 Hom.: 358 Cov.: 32

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.0660

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.00846

Gnomad SAS AF: 0.0255

Gnomad FIN AF: 0.0604

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0837

Gnomad OTH AF: 0.0678

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

GnomAD4 genome AF: 0.0586 AC: 8926 AN: 152332 Hom.: 358 Cov.: 32 AF XY: 0.0569 AC XY: 4235 AN XY: 74480

African (AFR) AF: 0.0150 AC: 625 AN: 41598

American (AMR) AF: 0.0659 AC: 1008 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 496 AN: 3472

East Asian (EAS) AF: 0.00848 AC: 44 AN: 5188

South Asian (SAS) AF: 0.0257 AC: 124 AN: 4822

European-Finnish (FIN) AF: 0.0604 AC: 641 AN: 10608

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0837 AC: 5692 AN: 68028

Other (OTH) AF: 0.0671 AC: 142 AN: 2116

Alfa AF: 0.0782 Hom.: 627

Bravo AF: 0.0571

Asia WGS AF: 0.0220 AC: 75 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	10
DANN	Benign	0.45
PhyloP100		0.035
Mutation Taster		=94/6	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: rs17182817; hg19: chr14-67146763;