chr11-617678-C-G

Variant names:

• chr11-617678-C-G
• rs1857033546
• NM_021924.5:c.2211G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021924.5(CDHR5):​c.2211G>C​(p.Lys737Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000375 in 1,333,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: CDHR5 NM_021924.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.568

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04164827).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDHR5	NM_021924.5	c.2211G>C	p.Lys737Asn	missense_variant	Exon 15 of 15	ENST00000397542.7	NP_068743.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDHR5	ENST00000397542.7	c.2211G>C	p.Lys737Asn	missense_variant	Exon 15 of 15	1	NM_021924.5	ENSP00000380676.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000375 AC: 5 AN: 1333526 Hom.: 0 Cov.: 36 AF XY: 0.00000306 AC XY: 2 AN XY: 653528

Gnomad4 AFR exome AF: 0.000135

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2211G>C (p.K737N) alteration is located in exon 15 (coding exon 15) of the CDHR5 gene. This alteration results from a G to C substitution at nucleotide position 2211, causing the lysine (K) at amino acid position 737 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.49
DANN	Benign	0.75
DEOGEN2	Benign	0.0053	T;T;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0094	N
LIST_S2	Benign	0.38	T;.;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.67	N;N;N
REVEL	Benign	0.023
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.42	T;T;T
Polyphen		0.40	B;B;B
Vest4		0.12
MutPred		0.31		Loss of methylation at K737 (P = 7e-04);Loss of methylation at K737 (P = 7e-04);.;
MVP		0.055
MPC		0.055
ClinPred		0.55	D
GERP RS		1.4
Varity_R		0.071
gMVP		0.12

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: rs1857033546; hg19: chr11-617678;