chr11-617574-G-T

Variant names:

• chr11-617574-G-T
• rs146458539
• NM_021924.5:c.2315C>A

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.2315C>A​(p.Thr772Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDHR5 NM_021924.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.516
• 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=0.029129028).

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.2315C>A	p.Thr772Lys	missense	Exon 15 of 15	NP_068743.3	Q9HBB8-1
	CDHR5	NM_001171968.3		c.2297C>A	p.Thr766Lys	missense	Exon 15 of 15	NP_001165439.2	Q9HBB8-4
	CDHR5	NM_031264.5		c.1733C>A	p.Thr578Lys	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.2315C>A	p.Thr772Lys	missense	Exon 15 of 15	ENSP00000380676.2	Q9HBB8-1
	CDHR5	ENST00000349570.11	TSL:1	c.1733C>A	p.Thr578Lys	missense	Exon 14 of 14	ENSP00000345726.7	Q9HBB8-2
	CDHR5	ENST00000872876.1		c.2399C>A	p.Thr800Lys	missense	Exon 16 of 16	ENSP00000542935.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000540 AC: 13 AN: 240958 AF XY: 0.0000530

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000380

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000891 AC: 13 AN: 1459190 Hom.: 0 Cov.: 36 AF XY: 0.00000964 AC XY: 7 AN XY: 725948

African (AFR) AF: 0.00 AC: 0 AN: 33388

American (AMR) AF: 0.000291 AC: 13 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111224

Other (OTH) AF: 0.00 AC: 0 AN: 60286

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000332 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	2.8
DANN	Benign	0.66
DEOGEN2	Benign	0.0054	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.52
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.019
Sift	Uncertain	0.013	D
Sift4G	Benign	0.27	T
Polyphen		0.24	B
Vest4		0.10
MutPred		0.28		Gain of methylation at T772 (P = 0.0188)
MVP		0.030
MPC		0.055
ClinPred		0.063	T
GERP RS		-0.15
Varity_R		0.082
gMVP		0.15
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs146458539; hg19: chr11-617574; COSMIC: COSV99042606; COSMIC: COSV99042606;