chr14-67179622-G-T

Variant names:

• chr14-67179622-G-T
• rs761412853
• NM_020806.5:c.2124G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP7

The NM_001377514.1(GPHN):​c.2184G>T​(p.Arg728Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000824 in 1,457,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R728R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: GPHN NM_001377514.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.44
• 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

ENSG00000307479 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP7: Synonymous conserved (PhyloP=2.44 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377514.1. 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.2124G>T	p.Arg708Arg	synonymous	Exon 22 of 23	NP_065857.1
	GPHN	NM_001377514.1		c.2184G>T	p.Arg728Arg	synonymous	Exon 24 of 25	NP_001364443.1
	GPHN	NM_001377515.1		c.2154G>T	p.Arg718Arg	synonymous	Exon 23 of 24	NP_001364444.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPHN	ENST00000478722.6	TSL:1 MANE Select	c.2124G>T	p.Arg708Arg	synonymous	Exon 22 of 23	ENSP00000417901.1
	GPHN	ENST00000315266.9	TSL:1	c.2025G>T	p.Arg675Arg	synonymous	Exon 21 of 22	ENSP00000312771.5
	GPHN	ENST00000960384.1		c.2295G>T	p.Arg765Arg	synonymous	Exon 24 of 25	ENSP00000630443.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251200 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000824 AC: 12 AN: 1457070 Hom.: 0 Cov.: 28 AF XY: 0.00000689 AC XY: 5 AN XY: 725250

African (AFR) AF: 0.00 AC: 0 AN: 33384

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000993 AC: 11 AN: 1107706

Other (OTH) AF: 0.0000166 AC: 1 AN: 60216

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	7.2
DANN	Benign	0.61
PhyloP100		2.4

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: rs761412853; hg19: chr14-67646339;