Genetic Variant CAND2:p.Thr90Ile (chr3-12807362-C-T) – 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_001162499.2(CAND2):c.269C>T(p.Thr90Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000416 in 1,551,748 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 0.00041 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00042 ( 0 hom. )

Consequence

CAND2
NM_001162499.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.05

Variant links:

Genes affected

CAND2 (HGNC:30689): (cullin associated and neddylation dissociated 2 (putative)) Predicted to enable TBP-class protein binding activity. Predicted to be involved in SCF complex assembly; positive regulation of transcription, DNA-templated; and protein ubiquitination. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

CAND2 links:

Genome browser will be placed here

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=0.034095973).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAND2	NM_001162499.2 link	c.269C>T	p.Thr90Ile	missense_variant	Exon 3 of 15	ENST00000456430.6	NP_001155971.1	O75155-1
CAND2	XM_011533504.3 link	c.197C>T	p.Thr66Ile	missense_variant	Exon 3 of 15		XP_011531806.1
CAND2	XM_011533503.3 link	c.269C>T	p.Thr90Ile	missense_variant	Exon 3 of 14		XP_011531805.1
CAND2	NM_012298.3 link	c.213-2697C>T		intron_variant	Intron 2 of 12		NP_036430.1	O75155-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAND2	ENST00000456430.6 link	c.269C>T	p.Thr90Ile	missense_variant	Exon 3 of 15	1	NM_001162499.2	ENSP00000387641.2		O75155-1

Frequencies

GnomAD3 genomes

AF:

0.000407

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000536

AC:

AN:

156690

Hom.:

AF XY:

0.000494

AC XY:

AN XY:

82990

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00158

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00101

Gnomad NFE exome

AF:

0.000412

Gnomad OTH exome

AF:

0.000682

GnomAD4 exome

AF:

0.000417

AC:

584

AN:

1399426

Hom.:

Cov.:

AF XY:

0.000406

AC XY:

280

AN XY:

690216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000316

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000771

Gnomad4 NFE exome

AF:

0.000430

Gnomad4 OTH exome

AF:

0.000465

GnomAD4 genome

AF:

0.000407

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.000472

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.000629

AC:

ExAC

AF:

0.000228

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.269C>T (p.T90I) alteration is located in exon 3 (coding exon 3) of the CAND2 gene. This alteration results from a C to T substitution at nucleotide position 269, causing the threonine (T) at amino acid position 90 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

Benign

0.13

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.078

Eigen

Benign

-0.065

Eigen_PC

Benign

0.053

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.020

MetaRNN

Benign

0.034

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.10

Sift

Benign

0.051

Sift4G

Benign

0.14

Polyphen

0.0030

Vest4

0.27

MVP

0.35

MPC

1.2

ClinPred

0.058

GERP RS

4.6

Varity_R

0.17

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over