5-179678722-A-T

Variant names:

• chr5-179678722-A-T
• rs779126754
• NM_001164444.2:c.590T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001164444.2(CBY3):​c.590T>A​(p.Met197Lys) 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 1,384,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M197T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CBY3 NM_001164444.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.51
• Publications: 0 publications found

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]

ENSG00000250999 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41064924).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164444.2. 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
	CBY3	NM_001164444.2	MANE Select	c.590T>A	p.Met197Lys	missense	Exon 2 of 2	NP_001157916.1	A6NI87

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBY3	ENST00000376974.5	TSL:2 MANE Select	c.590T>A	p.Met197Lys	missense	Exon 2 of 2	ENSP00000366173.4	A6NI87
	CANX	ENST00000681674.1		c.-59A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000505013.1	P27824-1
	CANX	ENST00000681712.1		c.-608A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000506061.1	P27824-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1384656 Hom.: 0 Cov.: 33 AF XY: 0.00000146 AC XY: 1 AN XY: 683270

African (AFR) AF: 0.00 AC: 0 AN: 31580

American (AMR) AF: 0.00 AC: 0 AN: 35692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35724

South Asian (SAS) AF: 0.00 AC: 0 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078694

Other (OTH) AF: 0.00 AC: 0 AN: 57898

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.0082	T
Eigen	Benign	-0.014
Eigen_PC	Benign	-0.037
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.15
Sift	Benign	0.20	T
Sift4G	Uncertain	0.0020	D
Vest4		0.63
MutPred		0.34		Gain of ubiquitination at M197 (P = 0.0128)
MVP		0.11
ClinPred		0.49	T
GERP RS		3.8
PromoterAI		0.076	Neutral
Varity_R		0.70
gMVP		0.34
Mutation Taster		=96/4	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: rs779126754; hg19: chr5-179105723;