11-617656-C-G

Variant names:

• chr11-617656-C-G
• rs756764471
• NM_021924.5:c.2233G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021924.5(CDHR5):​c.2233G>C​(p.Ala745Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000728 in 1,374,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A745T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: CDHR5 NM_021924.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043557346).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021924.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDHR5	NM_021924.5	MANE Select	c.2233G>C	p.Ala745Pro	missense	Exon 15 of 15	NP_068743.3	Q9HBB8-1
	CDHR5	NM_001171968.3		c.2215G>C	p.Ala739Pro	missense	Exon 15 of 15	NP_001165439.2	Q9HBB8-4
	CDHR5	NM_031264.5		c.1651G>C	p.Ala551Pro	missense	Exon 14 of 14	NP_112554.3	Q9HBB8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDHR5	ENST00000397542.7	TSL:1 MANE Select	c.2233G>C	p.Ala745Pro	missense	Exon 15 of 15	ENSP00000380676.2	Q9HBB8-1
	CDHR5	ENST00000349570.11	TSL:1	c.1651G>C	p.Ala551Pro	missense	Exon 14 of 14	ENSP00000345726.7	Q9HBB8-2
	CDHR5	ENST00000872876.1		c.2317G>C	p.Ala773Pro	missense	Exon 16 of 16	ENSP00000542935.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.28e-7 AC: 1 AN: 1374016 Hom.: 0 Cov.: 36 AF XY: 0.00000148 AC XY: 1 AN XY: 677380

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30634

American (AMR) AF: 0.00 AC: 0 AN: 31406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22838

East Asian (EAS) AF: 0.00 AC: 0 AN: 36338

South Asian (SAS) AF: 0.00 AC: 0 AN: 76496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5166

European-Non Finnish (NFE) AF: 9.32e-7 AC: 1 AN: 1072712

Other (OTH) AF: 0.00 AC: 0 AN: 56982

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.31
DANN	Benign	0.93
DEOGEN2	Benign	0.0034	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00050	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.1	T
PhyloP100		-1.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.60	N
REVEL	Benign	0.027
Sift	Benign	0.51	T
Sift4G	Benign	0.31	T
Polyphen		0.63	P
Vest4		0.033
MutPred		0.12		Gain of glycosylation at A745 (P = 0.0076)
MVP		0.076
MPC		0.051
ClinPred		0.37	T
GERP RS		-0.40
Varity_R		0.046
gMVP		0.17
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs756764471; hg19: chr11-617656;