8-74320911-C-T

Variant names:

• chr8-74320911-C-T
• rs140432891
• NM_020647.4:c.377G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_020647.4(JPH1):​c.377G>A​(p.Gly126Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000671 in 1,550,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G126A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: JPH1 NM_020647.4 missense, splice_region
• Scores: Splicing: ADA: 0.5587
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08
• Publications: 0 publications found

Genes affected

JPH1 (HGNC:14201): (junctophilin 1) Junctional complexes between the plasma membrane and endoplasmic/sarcoplasmic reticulum are a common feature of all excitable cell types and mediate cross talk between cell surface and intracellular ion channels. The protein encoded by this gene is a component of junctional complexes and is composed of a C-terminal hydrophobic segment spanning the endoplasmic/sarcoplasmic reticulum membrane and a remaining cytoplasmic domain that shows specific affinity for the plasma membrane. This gene is a member of the junctophilin gene family. [provided by RefSeq, Jul 2008]

GDAP1 (HGNC:15968): (ganglioside induced differentiation associated protein 1) This gene encodes a member of the ganglioside-induced differentiation-associated protein family, which may play a role in a signal transduction pathway during neuronal development. Mutations in this gene have been associated with various forms of Charcot-Marie-Tooth Disease and neuropathy. Two transcript variants encoding different isoforms and a noncoding variant have been identified for this gene. [provided by RefSeq, Feb 2012]

GDAP1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease axonal type 2K

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease recessive intermediate A

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal dominant Charcot-Marie-Tooth disease type 2K

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-Tooth disease type 4A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020647.4. 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
	JPH1	NM_020647.4	MANE Select	c.377G>A	p.Gly126Glu	missense splice_region	Exon 1 of 6	NP_065698.1	Q9HDC5
	JPH1	NM_001317830.2		c.377G>A	p.Gly126Glu	missense splice_region	Exon 1 of 6	NP_001304759.1	Q9HDC5
	JPH1	NM_001363050.1		c.377G>A	p.Gly126Glu	missense splice_region	Exon 1 of 6	NP_001349979.1	Q9HDC5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH1	ENST00000342232.5	TSL:1 MANE Select	c.377G>A	p.Gly126Glu	missense splice_region	Exon 1 of 6	ENSP00000344488.4	Q9HDC5
	JPH1	ENST00000519947.1	TSL:1	n.14+363G>A		intron	N/A	ENSP00000429652.1	E5RHU9
	JPH1	ENST00000868437.1		c.377G>A	p.Gly126Glu	missense splice_region	Exon 1 of 6	ENSP00000538496.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000575 AC: 11 AN: 191340 AF XY: 0.0000484

Gnomad AFR exome AF: 0.000233

Gnomad AMR exome AF: 0.0000364

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000680

Gnomad FIN exome AF: 0.0000525

Gnomad NFE exome AF: 0.0000232

Gnomad OTH exome AF: 0.000231

GnomAD4 exome AF: 0.0000665 AC: 93 AN: 1398308 Hom.: 0 Cov.: 31 AF XY: 0.0000579 AC XY: 40 AN XY: 690492

African (AFR) AF: 0.0000655 AC: 2 AN: 30544

American (AMR) AF: 0.0000261 AC: 1 AN: 38260

Ashkenazi Jewish (ASJ) AF: 0.0000455 AC: 1 AN: 21962

East Asian (EAS) AF: 0.000248 AC: 9 AN: 36298

South Asian (SAS) AF: 0.000117 AC: 9 AN: 76688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5460

European-Non Finnish (NFE) AF: 0.0000648 AC: 70 AN: 1080836

Other (OTH) AF: 0.0000173 AC: 1 AN: 57658

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74314

African (AFR) AF: 0.0000965 AC: 4 AN: 41440

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000690 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.000456 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000661 AC: 8

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		6.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.23	B
Vest4		0.78
MVP		0.54
MPC		2.2
ClinPred		0.83	D
GERP RS		4.1
PromoterAI		0.0036	Neutral
Varity_R		0.95
gMVP		0.71
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.56
dbscSNV1_RF	Benign	0.62
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: rs140432891; hg19: chr8-75233146; COSMIC: COSV105903986; COSMIC: COSV105903986;