5-179678740-G-A

Variant names:

• chr5-179678740-G-A
• NM_001164444.2:c.572C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001164444.2(CBY3):​c.572C>T​(p.Thr191Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,384,704 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CBY3 NM_001164444.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.86

Genes affected

CBY3 (HGNC:33278): (chibby family member 3)

CANX (HGNC:1473): (calnexin) This gene encodes a member of the calnexin family of molecular chaperones. The encoded protein is a calcium-binding, endoplasmic reticulum (ER)-associated protein that interacts transiently with newly synthesized N-linked glycoproteins, facilitating protein folding and assembly. It may also play a central role in the quality control of protein folding by retaining incorrectly folded protein subunits within the ER for degradation. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2018]

ACMG classification

Verdict is Uncertain_significance. Variant got 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
CBY3	NM_001164444.2	c.572C>T	p.Thr191Ile	missense_variant	Exon 2 of 2	ENST00000376974.5	NP_001157916.1
CBY3	XM_047417524.1	c.281C>T	p.Thr94Ile	missense_variant	Exon 2 of 2		XP_047273480.1
CANX	XM_011534665.4	c.-41G>A		5_prime_UTR_variant	Exon 1 of 15		XP_011532967.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBY3	ENST00000376974.5	c.572C>T	p.Thr191Ile	missense_variant	Exon 2 of 2	2	NM_001164444.2	ENSP00000366173.4
CANX	ENST00000681674	c.-41G>A		5_prime_UTR_variant	Exon 1 of 15			ENSP00000505013.1
CANX	ENST00000681712	c.-590G>A		5_prime_UTR_variant	Exon 1 of 16			ENSP00000506061.1
CANX	ENST00000681903	c.-548G>A		5_prime_UTR_variant	Exon 1 of 15			ENSP00000506509.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1384704 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 683300

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: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.572C>T (p.T191I) alteration is located in exon 2 (coding exon 2) of the CBY3 gene. This alteration results from a C to T substitution at nucleotide position 572, causing the threonine (T) at amino acid position 191 to be replaced by an isoleucine (I). 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	0.48
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.062
Eigen_PC	Benign	0.011
FATHMM_MKL	Benign	0.72	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.9	M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Vest4		0.61
MutPred		0.29		Loss of disorder (P = 0.0556);
MVP		0.10
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.33
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-179105741;