8-74244568-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_020647.4(JPH1):ā€‹c.1866C>Gā€‹(p.Ser622Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,612,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00016 ( 0 hom., cov: 32)
Exomes š‘“: 0.000016 ( 0 hom. )

Consequence

JPH1
NM_020647.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.73
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.026738524).
BS2
High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
JPH1NM_020647.4 linkuse as main transcriptc.1866C>G p.Ser622Arg missense_variant 4/6 ENST00000342232.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
JPH1ENST00000342232.5 linkuse as main transcriptc.1866C>G p.Ser622Arg missense_variant 4/61 NM_020647.4 P1
JPH1ENST00000519947.1 linkuse as main transcriptc.*1261C>G 3_prime_UTR_variant, NMD_transcript_variant 4/51
JPH1ENST00000518195.1 linkuse as main transcriptn.221C>G non_coding_transcript_exon_variant 1/34

Frequencies

GnomAD3 genomes
AF:
0.000164
AC:
25
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000603
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000280
AC:
7
AN:
250026
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135080
show subpopulations
Gnomad AFR exome
AF:
0.000431
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000164
AC:
24
AN:
1460590
Hom.:
0
Cov.:
32
AF XY:
0.0000124
AC XY:
9
AN XY:
726608
show subpopulations
Gnomad4 AFR exome
AF:
0.000659
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.000164
AC:
25
AN:
152306
Hom.:
0
Cov.:
32
AF XY:
0.000188
AC XY:
14
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.000601
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000162
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 05, 2023The c.1866C>G (p.S622R) alteration is located in exon 4 (coding exon 4) of the JPH1 gene. This alteration results from a C to G substitution at nucleotide position 1866, causing the serine (S) at amino acid position 622 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.15
T
Eigen
Benign
-0.35
Eigen_PC
Benign
-0.17
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.78
T
M_CAP
Benign
0.0089
T
MetaRNN
Benign
0.027
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.90
L
MutationTaster
Benign
0.82
D
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.21
N
REVEL
Benign
0.079
Sift
Benign
0.086
T
Sift4G
Benign
0.50
T
Polyphen
0.0010
B
Vest4
0.24
MutPred
0.25
Loss of phosphorylation at S622 (P = 0.0281);
MVP
0.28
MPC
0.11
ClinPred
0.051
T
GERP RS
3.1
Varity_R
0.059
gMVP
0.34

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.

Other links and lift over

dbSNP: rs139101026; hg19: chr8-75156803; API