1-228157753-G-C

Variant names:

• chr1-228157753-G-C
• rs762585789
• NM_020435.4:c.-6G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_020435.4(GJC2):​c.-6G>C variant causes a 5 prime UTR change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (0 hom., cov: 0)
  • Exomes 𝑓: 0.18 (489 hom.)
  • Failed GnomAD Quality Control
• Consequence: GJC2 NM_020435.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.69
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• hypomyelinating leukodystrophy 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• lymphatic malformation 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P
• hereditary spastic paraplegia 44

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• lymphatic malformation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 1-228157753-G-C is Benign according to our data. Variant chr1-228157753-G-C is described in ClinVar as Benign. ClinVar VariationId is 402902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJC2	NM_020435.4	c.-6G>C		5_prime_UTR_variant	Exon 2 of 2	ENST00000366714.3	NP_065168.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJC2	ENST00000366714.3	c.-6G>C		5_prime_UTR_variant	Exon 2 of 2	1	NM_020435.4	ENSP00000355675.2

Frequencies

GnomAD3 genomes AF: 0.297 AC: 9189 AN: 30906 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.305

GnomAD2 exomes AF: 0.446 AC: 36862 AN: 82652 AF XY: 0.446

Gnomad AFR exome AF: 0.406

Gnomad AMR exome AF: 0.490

Gnomad ASJ exome AF: 0.449

Gnomad EAS exome AF: 0.468

Gnomad FIN exome AF: 0.442

Gnomad NFE exome AF: 0.429

Gnomad OTH exome AF: 0.458

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.180 AC: 98728 AN: 549468 Hom.: 489 Cov.: 19 AF XY: 0.192 AC XY: 53456 AN XY: 278490

African (AFR) AF: 0.240 AC: 3286 AN: 13678

American (AMR) AF: 0.419 AC: 9533 AN: 22748

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 3057 AN: 11616

East Asian (EAS) AF: 0.219 AC: 3339 AN: 15254

South Asian (SAS) AF: 0.414 AC: 20625 AN: 49814

European-Finnish (FIN) AF: 0.229 AC: 5948 AN: 25950

Middle Eastern (MID) AF: 0.210 AC: 373 AN: 1778

European-Non Finnish (NFE) AF: 0.125 AC: 47981 AN: 384696

Other (OTH) AF: 0.192 AC: 4586 AN: 23934

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.297 AC: 9189 AN: 30890 Hom.: 0 Cov.: 0 AF XY: 0.271 AC XY: 4186 AN XY: 15474

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.307 AC: 2391 AN: 7788

American (AMR) AF: 0.153 AC: 565 AN: 3704

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 289 AN: 712

East Asian (EAS) AF: 0.184 AC: 179 AN: 974

South Asian (SAS) AF: 0.197 AC: 173 AN: 880

European-Finnish (FIN) AF: 0.142 AC: 416 AN: 2920

Middle Eastern (MID) AF: 0.152 AC: 7 AN: 46

European-Non Finnish (NFE) AF: 0.376 AC: 5019 AN: 13346

Other (OTH) AF: 0.304 AC: 124 AN: 408

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00159 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

not provided Benign:1

Mar 16, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.83
PhyloP100		5.7
Mutation Taster		=299/1	polymorphism

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

Other links and lift over

dbSNP: rs762585789; hg19: chr1-228345454;