1-228158705-C-T

Position:

chr1-228158705-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_020435.4(GJC2):c.947C>T(p.Pro316Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,179,386 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P316Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0071 ( 9 hom., cov: 32)

Exomes 𝑓: 0.00055 ( 7 hom. )

Consequence

GJC2
NM_020435.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.518

Variant links:

Genes affected

GJC2 (HGNC:17494): (gap junction protein gamma 2) This gene encodes a gap junction protein. Gap junction proteins are members of a large family of homologous connexins and comprise 4 transmembrane, 2 extracellular, and 3 cytoplasmic domains. This gene plays a key role in central myelination and is involved in peripheral myelination in humans. Defects in this gene are the cause of autosomal recessive Pelizaeus-Merzbacher-like disease-1. [provided by RefSeq, Jul 2008]

GJC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011750877).

BP6

Variant 1-228158705-C-T is Benign according to our data. Variant chr1-228158705-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235661.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}. Variant chr1-228158705-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00705 (1034/146612) while in subpopulation AFR AF= 0.0241 (984/40906). AF 95% confidence interval is 0.0228. There are 9 homozygotes in gnomad4. There are 519 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJC2	NM_020435.4 linkuse as main transcript	c.947C>T	p.Pro316Leu	missense_variant	2/2	ENST00000366714.3	NP_065168.2	Q5T442A0A654IBV7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJC2	ENST00000366714.3 linkuse as main transcript	c.947C>T	p.Pro316Leu	missense_variant	2/2	1	NM_020435.4	ENSP00000355675.2		Q5T442

Frequencies

GnomAD3 genomes

AF:

0.00699

AC:

1025

AN:

146544

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00244

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.0000303

Gnomad OTH

AF:

0.00495

GnomAD3 exomes

AF:

0.000915

AC:

AN:

17492

Hom.:

AF XY:

0.000467

AC XY:

AN XY:

10706

show subpopulations

Gnomad AFR exome

AF:

0.0317

Gnomad AMR exome

AF:

0.00167

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000482

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00183

GnomAD4 exome

AF:

0.000546

AC:

564

AN:

1032774

Hom.:

Cov.:

AF XY:

0.000512

AC XY:

255

AN XY:

498498

show subpopulations

Gnomad4 AFR exome

AF:

0.0258

Gnomad4 AMR exome

AF:

0.00239

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000148

Gnomad4 OTH exome

AF:

0.00120

GnomAD4 genome

AF:

0.00705

AC:

1034

AN:

146612

Hom.:

Cov.:

AF XY:

0.00728

AC XY:

519

AN XY:

71340

show subpopulations

Gnomad4 AFR

AF:

0.0241

Gnomad4 AMR

AF:

0.00243

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000303

Gnomad4 OTH

AF:

0.00491

ExAC

AF:

0.000463

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2019	This variant is associated with the following publications: (PMID: 24457200, 28732089, 20537300) -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 11, 2016	- -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.083

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.49

M_CAP

Pathogenic

0.85

MetaRNN

Benign

0.012

MetaSVM

Uncertain

0.31

MutationAssessor

Benign

0.32

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.12

REVEL

Uncertain

0.61

Sift

Benign

0.17

Sift4G

Benign

0.63

Polyphen

0.0010

Vest4

0.15

MVP

0.58

ClinPred

0.0027

GERP RS

-0.86

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.095

gMVP

0.25

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over