rs745809174

Variant names:

• chr1-228157745-G-C
• rs745809174
• NM_020435.4:c.-14G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-228157745-G-C
• chr1-228157745-G-A
• chr1-228157745-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_020435.4(GJC2):​c.-14G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (0 hom., cov: 0)
  • Exomes 𝑓: 0.16 (3789 hom.)
  • Failed GnomAD Quality Control
• Consequence: GJC2 NM_020435.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.278
• 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: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• lymphatic malformation 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-228157745-G-C is Benign according to our data. Variant chr1-228157745-G-C is described in ClinVar as Benign. ClinVar VariationId is 402901.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020435.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJC2	NM_020435.4	MANE Select	c.-14G>C		5_prime_UTR	Exon 2 of 2	NP_065168.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJC2	ENST00000366714.3	TSL:1 MANE Select	c.-14G>C		5_prime_UTR	Exon 2 of 2	ENSP00000355675.2	Q5T442
	GJC2	ENST00000886860.1		c.-14G>C		5_prime_UTR	Exon 2 of 2	ENSP00000556919.1
	GJC2	ENST00000963922.1		c.-14G>C		5_prime_UTR	Exon 2 of 2	ENSP00000633981.1

Frequencies

GnomAD3 genomes AF: 0.214 AC: 10434 AN: 48694 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.0969

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.125

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.237

GnomAD2 exomes AF: 0.492 AC: 40924 AN: 83214 AF XY: 0.492

Gnomad AFR exome AF: 0.488

Gnomad AMR exome AF: 0.499

Gnomad ASJ exome AF: 0.493

Gnomad EAS exome AF: 0.482

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.490

Gnomad OTH exome AF: 0.490

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.161 AC: 106630 AN: 662238 Hom.: 3789 Cov.: 21 AF XY: 0.172 AC XY: 58290 AN XY: 338530

African (AFR) AF: 0.202 AC: 3527 AN: 17454

American (AMR) AF: 0.377 AC: 10157 AN: 26918

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 3505 AN: 17398

East Asian (EAS) AF: 0.119 AC: 3589 AN: 30206

South Asian (SAS) AF: 0.438 AC: 22533 AN: 51406

European-Finnish (FIN) AF: 0.189 AC: 6257 AN: 33066

Middle Eastern (MID) AF: 0.163 AC: 407 AN: 2504

European-Non Finnish (NFE) AF: 0.115 AC: 51815 AN: 450874

Other (OTH) AF: 0.149 AC: 4840 AN: 32412

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.214 AC: 10437 AN: 48658 Hom.: 0 Cov.: 0 AF XY: 0.201 AC XY: 4810 AN XY: 23878

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

African (AFR) AF: 0.233 AC: 2705 AN: 11618

American (AMR) AF: 0.158 AC: 771 AN: 4866

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 319 AN: 1192

East Asian (EAS) AF: 0.0976 AC: 196 AN: 2008

South Asian (SAS) AF: 0.113 AC: 196 AN: 1730

European-Finnish (FIN) AF: 0.120 AC: 497 AN: 4154

Middle Eastern (MID) AF: 0.143 AC: 10 AN: 70

European-Non Finnish (NFE) AF: 0.251 AC: 5573 AN: 22228

Other (OTH) AF: 0.237 AC: 142 AN: 598

⚠️ 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: 0.00116 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.6
DANN	Benign	0.66
PhyloP100		-0.28
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs745809174; hg19: chr1-228345446;