chr5-179678771-G-C

Position:

• chr5-179678771-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164444.2(CBY3):​c.541C>G​(p.Leu181Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000306 in 1,536,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CBY3 NM_001164444.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.730

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14801234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBY3	NM_001164444.2	c.541C>G	p.Leu181Val	missense_variant	2/2	ENST00000376974.5	NP_001157916.1
CBY3	XM_047417524.1	c.250C>G	p.Leu84Val	missense_variant	2/2		XP_047273480.1
CANX	XM_011534665.4	c.-10G>C		5_prime_UTR_variant	1/15		XP_011532967.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBY3	ENST00000376974.5	c.541C>G	p.Leu181Val	missense_variant	2/2	2	NM_001164444.2	ENSP00000366173.4
CANX	ENST00000681674	c.-10G>C		5_prime_UTR_variant	1/15			ENSP00000505013.1
CANX	ENST00000681712	c.-559G>C		5_prime_UTR_variant	1/16			ENSP00000506061.1
CANX	ENST00000681903	c.-517G>C		5_prime_UTR_variant	1/15			ENSP00000506509.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.0000210 AC: 3 AN: 142718 Hom.: 0 AF XY: 0.0000393 AC XY: 3 AN XY: 76358

Gnomad AFR exome AF: 0.000263

Gnomad AMR exome AF: 0.0000407

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000173 AC: 24 AN: 1384722 Hom.: 0 Cov.: 33 AF XY: 0.0000176 AC XY: 12 AN XY: 683306

Gnomad4 AFR exome AF: 0.000507

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000121

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74368

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000261

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

May 27, 2022

The c.541C>G (p.L181V) alteration is located in exon 2 (coding exon 2) of the CBY3 gene. This alteration results from a C to G substitution at nucleotide position 541, causing the leucine (L) at amino acid position 181 to be replaced by a valine (V). 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	Benign	0.19
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.61	N
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.13
Sift	Uncertain	0.019	D
Sift4G	Pathogenic	0.0	D
Vest4		0.36
MutPred		0.19		Gain of methylation at K180 (P = 0.0383);
MVP		0.088
ClinPred		0.68	D
GERP RS		4.3
Varity_R		0.31
gMVP		0.31

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

LitVar

Other links and lift over

dbSNP: rs904804054; hg19: chr5-179105772;