rs144549731

Variant names:

• chr5-176575579-C-G
• rs144549731
• NM_017675.6:c.842C>G

Your query was ambiguous. Multiple possible variants found:

• chr5-176575579-C-G
• chr5-176575579-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017675.6(CDHR2):​c.842C>G​(p.Ser281Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. S281F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDHR2 NM_017675.6 missense, splice_region
• Scores: Splicing: ADA: 0.9466
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.968
• Publications: 0 publications found

Genes affected

CDHR2 (HGNC:18231): (cadherin related family member 2) This gene is a member of the protocadherin family, which represents a subset of the larger cadherin superfamily. The members of the protocadherin family encode non-classical cadherins that function as calcium-dependent cell-cell adhesion molecules. This protocadherin represents a new candidate for tumor suppression. Alternatively spliced transcript variants that encode the same protein have been identified. [provided by RefSeq, Jan 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDHR2	NM_017675.6	c.842C>G	p.Ser281Cys	missense_variant, splice_region_variant	Exon 10 of 32	ENST00000261944.10	NP_060145.3
CDHR2	NM_001171976.2	c.842C>G	p.Ser281Cys	missense_variant, splice_region_variant	Exon 10 of 32		NP_001165447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDHR2	ENST00000261944.10	c.842C>G	p.Ser281Cys	missense_variant, splice_region_variant	Exon 10 of 32	1	NM_017675.6	ENSP00000261944.5
CDHR2	ENST00000510636.5	c.842C>G	p.Ser281Cys	missense_variant, splice_region_variant	Exon 10 of 32	1		ENSP00000424565.1
CDHR2	ENST00000506348.1	n.889C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 31	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461724 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727166

⚠️ 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: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111882

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.72	.;.;T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.3	M;M;M
PhyloP100		0.97
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.54
MutPred		0.51		Loss of phosphorylation at Y278 (P = 0.174);Loss of phosphorylation at Y278 (P = 0.174);Loss of phosphorylation at Y278 (P = 0.174);
MVP		0.77
MPC		0.58
ClinPred		0.98	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.41
gMVP		0.23
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Benign	0.65
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: rs144549731; hg19: chr5-176002580;