14-66508574-G-T

Variant names:

• chr14-66508574-G-T
• rs764623558
• NM_020806.5:c.47G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020806.5(GPHN):​c.47G>T​(p.Arg16Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GPHN NM_020806.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.80

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]

ENSG00000258561 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPHN	NM_020806.5	c.47G>T	p.Arg16Leu	missense_variant	Exon 1 of 23	ENST00000478722.6	NP_065857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPHN	ENST00000478722.6	c.47G>T	p.Arg16Leu	missense_variant	Exon 1 of 23	1	NM_020806.5	ENSP00000417901.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;.;.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.9	L;L;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.6	D;N;D;N
REVEL	Benign	0.28
Sift	Uncertain	0.019	D;D;D;D
Sift4G	Benign	0.15	T;T;D;T
Polyphen		0.043	B;D;D;D
Vest4		0.62
MutPred		0.59		Gain of catalytic residue at D12 (P = 2e-04);Gain of catalytic residue at D12 (P = 2e-04);Gain of catalytic residue at D12 (P = 2e-04);Gain of catalytic residue at D12 (P = 2e-04);
MVP		0.39
MPC		0.87
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.72
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs764623558; hg19: chr14-66975292;