rs1043287274

Variant names:

• chr5-179678731-A-T
• rs1043287274
• NM_001164444.2:c.581T>A

Your query was ambiguous. Multiple possible variants found:

• chr5-179678731-A-T
• chr5-179678731-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164444.2(CBY3):​c.581T>A​(p.Met194Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,384,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M194I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CBY3 NM_001164444.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12664941).

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.581T>A	p.Met194Lys	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.581T>A	p.Met194Lys	missense	Exon 2 of 2	ENSP00000366173.4	A6NI87
	CANX	ENST00000681674.1		c.-50A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000505013.1	P27824-1
	CANX	ENST00000681712.1		c.-599A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000506061.1	P27824-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000140 AC: 2 AN: 142692 AF XY: 0.0000131

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000188

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000101 AC: 14 AN: 1384674 Hom.: 0 Cov.: 33 AF XY: 0.0000117 AC XY: 8 AN XY: 683282

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: 25166

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35726

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34984

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

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1078700

Other (OTH) AF: 0.0000173 AC: 1 AN: 57898

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.54	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.44	N
REVEL	Benign	0.080
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.013	D
Vest4		0.35
MutPred		0.34		Gain of ubiquitination at M194 (P = 0.0131)
MVP		0.067
ClinPred		0.27	T
GERP RS		3.1
PromoterAI		-0.23	Neutral
Varity_R		0.56
gMVP		0.42
Mutation Taster		=90/10	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: rs1043287274; hg19: chr5-179105732;