Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_020806.5(GPHN):c.1734T>C(p.Gly578Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,613,186 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 42 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 22 hom. )

Consequence

GPHN
NM_020806.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.774

Publications

1 publications found

Variant links:

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

GPHN links:

ENSG00000307479 (HGNC:):

ENSG00000307479 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 14-67122363-T-C is Benign according to our data. Variant chr14-67122363-T-C is described in ClinVar as Benign. ClinVar VariationId is 466202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.774 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0112 (1707/152260) while in subpopulation AFR AF = 0.0375 (1559/41550). AF 95% confidence interval is 0.036. There are 42 homozygotes in GnomAd4. There are 789 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 42 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GPHN	NM_020806.5	MANE Select	c.1734T>C	p.Gly578Gly	synonymous	Exon 17 of 23	NP_065857.1
GPHN	NM_001377514.1		c.1794T>C	p.Gly598Gly	synonymous	Exon 19 of 25	NP_001364443.1
GPHN	NM_001377515.1		c.1764T>C	p.Gly588Gly	synonymous	Exon 18 of 24	NP_001364444.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GPHN	ENST00000478722.6	TSL:1 MANE Select	c.1734T>C	p.Gly578Gly	synonymous	Exon 17 of 23	ENSP00000417901.1
GPHN	ENST00000315266.9	TSL:1	c.1635T>C	p.Gly545Gly	synonymous	Exon 16 of 22	ENSP00000312771.5
GPHN	ENST00000543237.5	TSL:2	c.1773T>C	p.Gly591Gly	synonymous	Exon 19 of 25	ENSP00000438404.1

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1704

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0376

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00615

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00909

GnomAD2 exomes

AF:

0.00312

AC:

784

AN:

251316

AF XY:

0.00222

show subpopulations

Gnomad AFR exome

AF:

0.0397

Gnomad AMR exome

AF:

0.00246

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.00129

AC:

1887

AN:

1460926

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

839

AN XY:

726818

show subpopulations

African (AFR)

AF:

0.0406

AC:

1358

AN:

33444

American (AMR)

AF:

0.00224

AC:

100

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000536

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.000197

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000166

AC:

184

AN:

1111226

Other (OTH)

AF:

0.00315

AC:

190

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

181

272

362

453

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0112

AC:

1707

AN:

152260

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

789

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0375

AC:

1559

AN:

41550

American (AMR)

AF:

0.00614

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000623

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68010

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

163

245

326

408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00529

Hom.:

Bravo

AF:

0.0128

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

7.4

(source)

DANN

Benign

0.72

PhyloP100

0.77

Mutation Taster

=84/16

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over