rs2740375

chr11-618998-G-Achr11-618998-G-Cchr11-618998-G-T

Variant summary

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

The NM_021924.5(CDHR5):c.1561C>T(p.Pro521Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 1,612,530 control chromosomes in the GnomAD database, including 242,696 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.48 (18940 hom., cov: 29)
  • Exomes 𝑓: 0.55 (223756 hom.)
• Consequence: CDHR5 NM_021924.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.307

Genes affected

CDHR5 (HGNC:7521): (cadherin related family member 5) This gene is a novel mucin-like gene that is a member of the cadherin superfamily. While encoding nonpolymorphic tandem repeats rich in proline, serine and threonine similar to mucin proteins, the gene also contains sequence encoding calcium-binding motifs found in all cadherins. The role of the hybrid extracellular region and the specific function of this protein have not yet been determined. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.9095008E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.676 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDHR5	NM_021924.5	c.1561C>T	p.Pro521Ser	missense_variant	13/15	ENST00000397542.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDHR5	ENST00000397542.7	c.1561C>T	p.Pro521Ser	missense_variant	13/15	1	NM_021924.5	P2

Frequencies

GnomAD3 genomes AF: 0.484 AC: 73107 AN: 150950 Hom.: 18946 Cov.: 29

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.657

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.528

Gnomad EAS AF: 0.696

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.666

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.491

GnomAD3 exomes AF: 0.542 AC: 135495 AN: 250138 Hom.: 38082 AF XY: 0.551 AC XY: 74736 AN XY: 135518

Gnomad AFR exome AF: 0.286

Gnomad AMR exome AF: 0.416

Gnomad ASJ exome AF: 0.539

Gnomad EAS exome AF: 0.690

Gnomad SAS exome AF: 0.578

Gnomad FIN exome AF: 0.651

Gnomad NFE exome AF: 0.561

Gnomad OTH exome AF: 0.554

GnomAD4 exome AF: 0.550 AC: 803258 AN: 1461466 Hom.: 223756 Cov.: 71 AF XY: 0.552 AC XY: 401240 AN XY: 727052

Gnomad4 AFR exome AF: 0.281

Gnomad4 AMR exome AF: 0.421

Gnomad4 ASJ exome AF: 0.539

Gnomad4 EAS exome AF: 0.731

Gnomad4 SAS exome AF: 0.575

Gnomad4 FIN exome AF: 0.637

Gnomad4 NFE exome AF: 0.551

Gnomad4 OTH exome AF: 0.540

GnomAD4 genome AF: 0.484 AC: 73111 AN: 151064 Hom.: 18940 Cov.: 29 AF XY: 0.491 AC XY: 36239 AN XY: 73764

Gnomad4 AFR AF: 0.290

Gnomad4 AMR AF: 0.446

Gnomad4 ASJ AF: 0.528

Gnomad4 EAS AF: 0.695

Gnomad4 SAS AF: 0.589

Gnomad4 FIN AF: 0.666

Gnomad4 NFE AF: 0.555

Gnomad4 OTH AF: 0.490

Alfa AF: 0.488 Hom.: 7381

Bravo AF: 0.461

TwinsUK AF: 0.543 AC: 2015

ALSPAC AF: 0.548 AC: 2113

ESP6500AA AF: 0.288 AC: 1270

ESP6500EA AF: 0.538 AC: 4629

ExAC AF: 0.543 AC: 65915

Asia WGS AF: 0.577 AC: 2008 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	1.1
Dann	Benign	0.65
DEOGEN2	Benign	0.0053	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.34	T;.
MetaRNN	Benign	0.0000029	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.27	N;N
REVEL	Benign	0.0090
Sift	Benign	0.41	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.093	B;B
Vest4		0.19
MPC		0.057
ClinPred		0.0056	T
GERP RS		1.6
Varity_R		0.021
gMVP		0.29

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: rs2740375; hg19: chr11-618998; COSMIC: COSV57641239; COSMIC: COSV57641239;