14-66636861-C-T

Variant names:

• chr14-66636861-C-T
• rs7149265
• NM_020806.5:c.65-44246C>T

Variant summary

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

The NM_020806.5(GPHN):​c.65-44246C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 152,028 control chromosomes in the GnomAD database, including 22,155 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 0.50 (22155 hom., cov: 32)
• Consequence: GPHN NM_020806.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.289
• Publications: 6 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 = 0.791 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPHN	NM_020806.5	MANE Select	c.65-44246C>T		intron	N/A	NP_065857.1	Q9NQX3-2
	GPHN	NM_001377514.1		c.65-44246C>T		intron	N/A	NP_001364443.1
	GPHN	NM_001377515.1		c.65-44246C>T		intron	N/A	NP_001364444.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPHN	ENST00000478722.6	TSL:1 MANE Select	c.65-44246C>T		intron	N/A	ENSP00000417901.1	Q9NQX3-2
	GPHN	ENST00000315266.9	TSL:1	c.65-44246C>T		intron	N/A	ENSP00000312771.5	Q9NQX3-1
	GPHN	ENST00000960384.1		c.65-44246C>T		intron	N/A	ENSP00000630443.1

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76245 AN: 151910 Hom.: 22093 Cov.: 32

Gnomad AFR AF: 0.798

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.367

Gnomad EAS AF: 0.531

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.340

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.352

Gnomad OTH AF: 0.478

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

GnomAD4 genome AF: 0.502 AC: 76375 AN: 152028 Hom.: 22155 Cov.: 32 AF XY: 0.501 AC XY: 37199 AN XY: 74302

African (AFR) AF: 0.798 AC: 33116 AN: 41492

American (AMR) AF: 0.523 AC: 7989 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 1273 AN: 3470

East Asian (EAS) AF: 0.531 AC: 2745 AN: 5168

South Asian (SAS) AF: 0.455 AC: 2196 AN: 4830

European-Finnish (FIN) AF: 0.340 AC: 3588 AN: 10542

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.352 AC: 23928 AN: 67940

Other (OTH) AF: 0.480 AC: 1015 AN: 2114

Alfa AF: 0.399 Hom.: 8319

Bravo AF: 0.529

Asia WGS AF: 0.503 AC: 1748 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	0.63
DANN	Benign	0.39
PhyloP100		-0.29
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: rs7149265; hg19: chr14-67103579;