11-619789-T-G

Variant names:

• chr11-619789-T-G
• rs2246614
• NM_021924.5:c.1071A>C

Variant summary

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

The NM_021924.5(CDHR5):​c.1071A>C​(p.Arg357Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 1,606,594 control chromosomes in the GnomAD database, including 324,052 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.59 (27158 hom., cov: 35)
  • Exomes 𝑓: 0.64 (296894 hom.)
• Consequence: CDHR5 NM_021924.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0960

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=3.6715473E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDHR5	NM_021924.5	c.1071A>C	p.Arg357Ser	missense_variant	Exon 10 of 15	ENST00000397542.7	NP_068743.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDHR5	ENST00000397542.7	c.1071A>C	p.Arg357Ser	missense_variant	Exon 10 of 15	1	NM_021924.5	ENSP00000380676.2

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89820 AN: 152036 Hom.: 27153 Cov.: 35

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.703

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.677

Gnomad EAS AF: 0.718

Gnomad SAS AF: 0.709

Gnomad FIN AF: 0.721

Gnomad MID AF: 0.640

Gnomad NFE AF: 0.640

Gnomad OTH AF: 0.614

GnomAD3 exomes AF: 0.627 AC: 146063 AN: 232808 Hom.: 46758 AF XY: 0.641 AC XY: 82069 AN XY: 128048

Gnomad AFR exome AF: 0.454

Gnomad AMR exome AF: 0.472

Gnomad ASJ exome AF: 0.680

Gnomad EAS exome AF: 0.707

Gnomad SAS exome AF: 0.710

Gnomad FIN exome AF: 0.707

Gnomad NFE exome AF: 0.644

Gnomad OTH exome AF: 0.652

GnomAD4 exome AF: 0.637 AC: 926196 AN: 1454438 Hom.: 296894 Cov.: 51 AF XY: 0.641 AC XY: 463671 AN XY: 723566

Gnomad4 AFR exome AF: 0.447

Gnomad4 AMR exome AF: 0.482

Gnomad4 ASJ exome AF: 0.681

Gnomad4 EAS exome AF: 0.743

Gnomad4 SAS exome AF: 0.708

Gnomad4 FIN exome AF: 0.697

Gnomad4 NFE exome AF: 0.635

Gnomad4 OTH exome AF: 0.642

GnomAD4 genome AF: 0.591 AC: 89851 AN: 152156 Hom.: 27158 Cov.: 35 AF XY: 0.597 AC XY: 44378 AN XY: 74380

Gnomad4 AFR AF: 0.457

Gnomad4 AMR AF: 0.531

Gnomad4 ASJ AF: 0.677

Gnomad4 EAS AF: 0.717

Gnomad4 SAS AF: 0.710

Gnomad4 FIN AF: 0.721

Gnomad4 NFE AF: 0.640

Gnomad4 OTH AF: 0.612

Alfa AF: 0.639 Hom.: 51875

Bravo AF: 0.572

TwinsUK AF: 0.636 AC: 2360

ALSPAC AF: 0.631 AC: 2431

ESP6500AA AF: 0.448 AC: 1971

ESP6500EA AF: 0.623 AC: 5357

ExAC AF: 0.625 AC: 75262

Asia WGS AF: 0.660 AC: 2299 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.2
DANN	Benign	0.68
DEOGEN2	Benign	0.0026	T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00016	N
LIST_S2	Benign	0.13	T;.;T
MetaRNN	Benign	0.0000037	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.0	N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	2.5	N;N;N
REVEL	Benign	0.035
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.041
MutPred		0.46		Loss of MoRF binding (P = 0.0231);Loss of MoRF binding (P = 0.0231);Loss of MoRF binding (P = 0.0231);
MPC		0.046
ClinPred		0.0017	T
GERP RS		2.0
Varity_R		0.084
gMVP		0.34

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: rs2246614; hg19: chr11-619789; COSMIC: COSV57641662; COSMIC: COSV57641662;