dbSNP rs1043287274: CBY3:p.Met194Thr (chr5-179678731-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001164444.2(CBY3):c.581T>C(p.Met194Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,384,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CBY3
NM_001164444.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.83

Variant links:

Genes affected

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

CBY3 links:

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]

CANX links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.038987666).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBY3	NM_001164444.2 link	c.581T>C	p.Met194Thr	missense_variant	Exon 2 of 2	ENST00000376974.5	NP_001157916.1	A6NI87
CBY3	XM_047417524.1 link	c.290T>C	p.Met97Thr	missense_variant	Exon 2 of 2		XP_047273480.1
CANX	XM_011534665.4 link	c.-50A>G		5_prime_UTR_variant	Exon 1 of 15		XP_011532967.1	P27824-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CBY3	ENST00000376974.5 link	c.581T>C	p.Met194Thr	missense_variant	Exon 2 of 2	2	NM_001164444.2	ENSP00000366173.4	A6NI87
CANX	ENST00000681674 link	c.-50A>G		5_prime_UTR_variant	Exon 1 of 15			ENSP00000505013.1	P27824-1
CANX	ENST00000681712 link	c.-599A>G		5_prime_UTR_variant	Exon 1 of 16			ENSP00000506061.1	P27824-1
CANX	ENST00000681903 link	c.-557A>G		5_prime_UTR_variant	Exon 1 of 15			ENSP00000506509.1	P27824-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000701

AC:

AN:

142692

Hom.:

AF XY:

0.0000131

AC XY:

AN XY:

76356

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000144

AC:

AN:

1384674

Hom.:

Cov.:

AF XY:

0.00000293

AC XY:

AN XY:

683282

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

9.27e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.012

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.026

M_CAP

Benign

0.033

MetaRNN

Benign

0.039

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-2.5

PrimateAI

Uncertain

0.54

PROVEAN

Benign

4.9

REVEL

Benign

0.098

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.22

MutPred

0.35

Gain of glycosylation at M194 (P = 0.0191);

MVP

0.030

ClinPred

0.084

GERP RS

3.1

Varity_R

0.058

gMVP

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over