19-10395335-G-A

Position:

• chr19-10395335-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_007065.4(CDC37):​c.496C>T​(p.Arg166Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,588 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CDC37 NM_007065.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.06

Genes affected

CDC37 (HGNC:1735): (cell division cycle 37, HSP90 cochaperone) The protein encoded by this gene is highly similar to Cdc 37, a cell division cycle control protein of Sacchromyces cerevisiae. This protein is a molecular chaperone with specific function in cell signal transduction. It has been shown to form complex with Hsp90 and a variety of protein kinases including CDK4, CDK6, SRC, RAF-1, MOK, as well as eIF2 alpha kinases. It is thought to play a critical role in directing Hsp90 to its target kinases. [provided by RefSeq, Jul 2008]

CDC37 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC37	NM_007065.4	c.496C>T	p.Arg166Cys	missense_variant	4/8	ENST00000222005.7	NP_008996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC37	ENST00000222005.7	c.496C>T	p.Arg166Cys	missense_variant	4/8	1	NM_007065.4	ENSP00000222005.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461588 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727106

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2024

The c.496C>T (p.R166C) alteration is located in exon 4 (coding exon 4) of the CDC37 gene. This alteration results from a C to T substitution at nucleotide position 496, causing the arginine (R) at amino acid position 166 to be replaced by a cysteine (C). 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.4	D;.
REVEL	Benign	0.27
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		1.0	D;.
Vest4		0.59
MutPred		0.50		Gain of catalytic residue at M164 (P = 2e-04);.;
MVP		0.69
MPC		1.7
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.63
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs866354313; hg19: chr19-10506011;