10-30026252-G-A

Position:

• chr10-30026252-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020848.4(JCAD):​c.3896C>T​(p.Pro1299Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,613,898 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (14 hom.)
• Consequence: JCAD NM_020848.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.862

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033407807).
• BP6: Variant 10-30026252-G-A is Benign according to our data. Variant chr10-30026252-G-A is described in ClinVar as [Benign]. Clinvar id is 786153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00601 (916/152324) while in subpopulation AFR AF= 0.0206 (855/41572). AF 95% confidence interval is 0.0194. There are 8 homozygotes in gnomad4. There are 419 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JCAD	NM_020848.4	c.3896C>T	p.Pro1299Leu	missense_variant	3/4	ENST00000375377.2	NP_065899.1
JCAD	NM_001350022.2	c.3896C>T	p.Pro1299Leu	missense_variant	4/5		NP_001336951.1
JCAD	NM_001350001.2	c.3482C>T	p.Pro1161Leu	missense_variant	4/5		NP_001336930.1
JCAD	NM_001350021.2	c.3482C>T	p.Pro1161Leu	missense_variant	4/5		NP_001336950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JCAD	ENST00000375377.2	c.3896C>T	p.Pro1299Leu	missense_variant	3/4	5	NM_020848.4	ENSP00000364526.1

Frequencies

GnomAD3 genomes AF: 0.00593 AC: 903 AN: 152206 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

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: 0.000118

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00146 AC: 363 AN: 249152 Hom.: 5 AF XY: 0.00110 AC XY: 149 AN XY: 135206

Gnomad AFR exome AF: 0.0200

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000619

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000598 AC: 874 AN: 1461574 Hom.: 14 Cov.: 30 AF XY: 0.000518 AC XY: 377 AN XY: 727106

Gnomad4 AFR exome AF: 0.0200

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.00162

GnomAD4 genome AF: 0.00601 AC: 916 AN: 152324 Hom.: 8 Cov.: 32 AF XY: 0.00562 AC XY: 419 AN XY: 74490

Gnomad4 AFR AF: 0.0206

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00105 Hom.: 1

Bravo AF: 0.00639

ESP6500AA AF: 0.0144 AC: 54

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00166 AC: 201

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 09, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.76
DEOGEN2	Benign	0.0033	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.062
Sift	Benign	1.0	T
Sift4G	Benign	0.76	T
Polyphen		0.36	B
Vest4		0.12
MVP		0.095
MPC		0.19
ClinPred		0.015	T
GERP RS		3.2
Varity_R		0.027
gMVP		0.039

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: rs76622613; hg19: chr10-30315181; COSMIC: COSV99057523;