20-61254865-G-A

Position:

• chr20-61254865-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_001794.5(CDH4):​c.97G>A​(p.Ala33Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,612,986 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (12 hom.)
• Consequence: CDH4 NM_001794.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.17

Genes affected

CDH4 (HGNC:1763): (cadherin 4) This gene is a classical cadherin from the cadherin superfamily. The encoded protein is a calcium-dependent cell-cell adhesion glycoprotein comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Based on studies in chicken and mouse, this cadherin is thought to play an important role during brain segmentation and neuronal outgrowth. In addition, a role in kidney and muscle development is indicated. Of particular interest are studies showing stable cis-heterodimers of cadherins 2 and 4 in cotransfected cell lines. Previously thought to interact in an exclusively homophilic manner, this is the first evidence of cadherin heterodimerization. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008261234).
• BP6: Variant 20-61254865-G-A is Benign according to our data. Variant chr20-61254865-G-A is described in ClinVar as [Benign]. Clinvar id is 769098.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 = 0.00724 (1103/152308) while in subpopulation AFR AF= 0.0251 (1041/41550). AF 95% confidence interval is 0.0238. There are 8 homozygotes in gnomad4. There are 535 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1103 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH4	NM_001794.5	c.97G>A	p.Ala33Thr	missense_variant	2/16	ENST00000614565.5	NP_001785.2
CDH4	XM_047439812.1	c.-126G>A		5_prime_UTR_variant	2/16		XP_047295768.1
CDH4	XM_047439813.1	c.-126G>A		5_prime_UTR_variant	2/16		XP_047295769.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH4	ENST00000614565.5	c.97G>A	p.Ala33Thr	missense_variant	2/16	1	NM_001794.5	ENSP00000484928	P1

Frequencies

GnomAD3 genomes AF: 0.00723 AC: 1101 AN: 152188 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00187 AC: 470 AN: 251464 Hom.: 3 AF XY: 0.00145 AC XY: 197 AN XY: 135912

Gnomad AFR exome AF: 0.0259

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000744 AC: 1087 AN: 1460678 Hom.: 12 Cov.: 30 AF XY: 0.000623 AC XY: 453 AN XY: 726770

Gnomad4 AFR exome AF: 0.0267

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.00724 AC: 1103 AN: 152308 Hom.: 8 Cov.: 33 AF XY: 0.00718 AC XY: 535 AN XY: 74466

Gnomad4 AFR AF: 0.0251

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00124 Hom.: 3

Bravo AF: 0.00803

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00229 AC: 278

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

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	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N
MutationTaster	Benign	0.69	N
PrimateAI	Benign	0.43	T
Sift4G	Benign	0.13	T
Polyphen		0.0070	B
Vest4		0.21
MVP		0.37
ClinPred		0.015	T
GERP RS		1.0
Varity_R		0.056
gMVP		0.33

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: rs144744391; hg19: chr20-59829921;