10-30027143-C-G

Position:

• chr10-30027143-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020848.4(JCAD):​c.3005G>C​(p.Ser1002Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,613,950 control chromosomes in the GnomAD database, including 136,854 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.33 (9942 hom., cov: 32)
  • Exomes 𝑓: 0.41 (126912 hom.)
• Consequence: JCAD NM_020848.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.153

Genes affected

JCAD (HGNC:29283): (junctional cadherin 5 associated) This gene encodes an endothelial cell-to-cell junction protein. Naturally occurring mutations in this gene are associated with coronary artery disease, late onset alzheimer disease, and emphysema distribution. [provided by RefSeq, Mar 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.4336576E-4).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JCAD	NM_020848.4	c.3005G>C	p.Ser1002Thr	missense_variant	3/4	ENST00000375377.2	NP_065899.1
JCAD	NM_001350022.2	c.3005G>C	p.Ser1002Thr	missense_variant	4/5		NP_001336951.1
JCAD	NM_001350001.2	c.2591G>C	p.Ser864Thr	missense_variant	4/5		NP_001336930.1
JCAD	NM_001350021.2	c.2591G>C	p.Ser864Thr	missense_variant	4/5		NP_001336950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JCAD	ENST00000375377.2	c.3005G>C	p.Ser1002Thr	missense_variant	3/4	5	NM_020848.4	ENSP00000364526.1

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50394 AN: 151984 Hom.: 9938 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.373

GnomAD3 exomes AF: 0.377 AC: 94037 AN: 249440 Hom.: 19161 AF XY: 0.381 AC XY: 51496 AN XY: 135334

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.429

Gnomad ASJ exome AF: 0.324

Gnomad EAS exome AF: 0.171

Gnomad SAS exome AF: 0.312

Gnomad FIN exome AF: 0.453

Gnomad NFE exome AF: 0.436

Gnomad OTH exome AF: 0.414

GnomAD4 exome AF: 0.410 AC: 598984 AN: 1461848 Hom.: 126912 Cov.: 73 AF XY: 0.409 AC XY: 297784 AN XY: 727228

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.429

Gnomad4 ASJ exome AF: 0.331

Gnomad4 EAS exome AF: 0.165

Gnomad4 SAS exome AF: 0.319

Gnomad4 FIN exome AF: 0.447

Gnomad4 NFE exome AF: 0.435

Gnomad4 OTH exome AF: 0.384

GnomAD4 genome AF: 0.331 AC: 50392 AN: 152102 Hom.: 9942 Cov.: 32 AF XY: 0.335 AC XY: 24928 AN XY: 74344

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.422

Gnomad4 ASJ AF: 0.333

Gnomad4 EAS AF: 0.167

Gnomad4 SAS AF: 0.303

Gnomad4 FIN AF: 0.457

Gnomad4 NFE AF: 0.436

Gnomad4 OTH AF: 0.371

Alfa AF: 0.410 Hom.: 10048

Bravo AF: 0.320

TwinsUK AF: 0.429 AC: 1589

ALSPAC AF: 0.424 AC: 1636

ESP6500AA AF: 0.119 AC: 454

ESP6500EA AF: 0.425 AC: 3503

ExAC AF: 0.369 AC: 44582

Asia WGS AF: 0.222 AC: 774 AN: 3478

EpiCase AF: 0.436

EpiControl AF: 0.436

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.7
DANN	Benign	0.76
DEOGEN2	Benign	0.0045	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.00024	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.058
Sift	Benign	0.89	T
Sift4G	Benign	0.68	T
Polyphen		0.058	B
Vest4		0.032
MPC		0.21
ClinPred		0.0023	T
GERP RS		-0.72
Varity_R		0.039
gMVP		0.088

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

Other links and lift over

dbSNP: rs3739998; hg19: chr10-30316072; COSMIC: COSV64759810;