chr14-66508553-C-G

Variant names:

• chr14-66508553-C-G
• rs150226537
• NM_020806.5:c.26C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001377514.1(GPHN):​c.26C>G​(p.Thr9Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00107 in 1,614,134 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T9A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: GPHN NM_001377514.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.94
• Publications: 5 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

ENSG00000258561 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0118897855).
• BP6: Variant 14-66508553-C-G is Benign according to our data. Variant chr14-66508553-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 466208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00106 (162/152370) while in subpopulation NFE AF = 0.00171 (116/68030). AF 95% confidence interval is 0.00145. There are 0 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.26C>G	p.Thr9Ser	missense	Exon 1 of 23	NP_065857.1
	GPHN	NM_001377514.1		c.26C>G	p.Thr9Ser	missense	Exon 1 of 25	NP_001364443.1
	GPHN	NM_001377515.1		c.26C>G	p.Thr9Ser	missense	Exon 1 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.26C>G	p.Thr9Ser	missense	Exon 1 of 23	ENSP00000417901.1
	GPHN	ENST00000315266.9	TSL:1	c.26C>G	p.Thr9Ser	missense	Exon 1 of 22	ENSP00000312771.5
	GPHN	ENST00000960384.1		c.26C>G	p.Thr9Ser	missense	Exon 1 of 25	ENSP00000630443.1

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 162 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00170

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00136 AC: 342 AN: 251468 AF XY: 0.00148

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00218

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00108 AC: 1572 AN: 1461764 Hom.: 1 Cov.: 30 AF XY: 0.00116 AC XY: 842 AN XY: 727194

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.00163 AC: 73 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000696 AC: 60 AN: 86254

European-Finnish (FIN) AF: 0.000393 AC: 21 AN: 53418

Middle Eastern (MID) AF: 0.00589 AC: 34 AN: 5768

European-Non Finnish (NFE) AF: 0.00117 AC: 1301 AN: 1111902

Other (OTH) AF: 0.00131 AC: 79 AN: 60390

GnomAD4 genome AF: 0.00106 AC: 162 AN: 152370 Hom.: 0 Cov.: 33 AF XY: 0.00113 AC XY: 84 AN XY: 74506

African (AFR) AF: 0.000288 AC: 12 AN: 41596

American (AMR) AF: 0.00124 AC: 19 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.000470 AC: 5 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00171 AC: 116 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00120 Hom.: 0

Bravo AF: 0.00111

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00137 AC: 166

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00373

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A (2)
-	-	1	GPHN-related disorder (1)
-	-	1	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.069
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		6.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.047
Sift	Benign	0.41	T
Sift4G	Benign	0.74	T
Polyphen		0.0030	B
Vest4		0.18
MutPred		0.43		Gain of catalytic residue at D12 (P = 0.0024)
MVP		0.39
MPC		0.59
ClinPred		0.048	T
GERP RS		4.3
PromoterAI		-0.13	Neutral
Varity_R		0.13
gMVP		0.49
Mutation Taster		=96/4	polymorphism

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: rs150226537; hg19: chr14-66975271;