20-61254848-C-T

Position:

• chr20-61254848-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001794.5(CDH4):​c.80C>T​(p.Thr27Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,609,218 control chromosomes in the GnomAD database, including 7 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (7 hom.)
• Consequence: CDH4 NM_001794.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.668

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009611875).
• BP6: Variant 20-61254848-C-T is Benign according to our data. Variant chr20-61254848-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 775438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 353 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH4	NM_001794.5	c.80C>T	p.Thr27Ile	missense_variant	2/16	ENST00000614565.5	NP_001785.2
CDH4	XM_047439812.1	c.-143C>T		5_prime_UTR_variant	2/16		XP_047295768.1
CDH4	XM_047439813.1	c.-143C>T		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.80C>T	p.Thr27Ile	missense_variant	2/16	1	NM_001794.5	ENSP00000484928	P1

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 352 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00577

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00123 AC: 310 AN: 251448 Hom.: 2 AF XY: 0.00127 AC XY: 173 AN XY: 135902

Gnomad AFR exome AF: 0.00542

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000967

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00101 AC: 1470 AN: 1456902 Hom.: 7 Cov.: 29 AF XY: 0.00105 AC XY: 758 AN XY: 725166

Gnomad4 AFR exome AF: 0.00719

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.00264

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000724

Gnomad4 OTH exome AF: 0.00284

GnomAD4 genome AF: 0.00232 AC: 353 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.00224 AC XY: 167 AN XY: 74482

Gnomad4 AFR AF: 0.00577

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00123 Hom.: 1

Bravo AF: 0.00276

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00129 AC: 157

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00136

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 19, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.46	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.28
MVP		0.29
ClinPred		0.015	T
GERP RS		1.2
Varity_R		0.037
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149390633; hg19: chr20-59829904; COSMIC: COSV99082084;