Genetic Variant CDRT15:p.Ile82Thr (chr17-14236589-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_001007530.3(CDRT15):c.245T>C(p.Ile82Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,508,658 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 (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

CDRT15
NM_001007530.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.65

Variant links:

Genes affected

CDRT15 (HGNC:14395): (CMT1A duplicated region transcript 15)

CDRT15 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=0.009784639).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDRT15	NM_001007530.3 link	c.245T>C	p.Ile82Thr	missense_variant	Exon 1 of 3	ENST00000420162.7	NP_001007531.1
CDRT15	NM_001348781.2 link	c.64+107T>C		intron_variant	Intron 1 of 2		NP_001335710.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDRT15	ENST00000420162.7 link	c.245T>C	p.Ile82Thr	missense_variant	Exon 1 of 3	1	NM_001007530.3	ENSP00000402355.3		Q96T59
CDRT15	ENST00000431716.2 link	c.64+107T>C		intron_variant	Intron 1 of 2	1		ENSP00000399575.2		F2Z3C1

Frequencies

GnomAD3 genomes

AF:

0.000297

AC:

AN:

151648

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000437

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.00252

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000255

AC:

AN:

117740

Hom.:

AF XY:

0.000330

AC XY:

AN XY:

60568

show subpopulations

Gnomad AFR exome

AF:

0.000121

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000350

Gnomad SAS exome

AF:

0.00167

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000630

Gnomad OTH exome

AF:

0.000318

GnomAD4 exome

AF:

0.000141

AC:

191

AN:

1356892

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

120

AN XY:

665048

show subpopulations

Gnomad4 AFR exome

AF:

0.000328

Gnomad4 AMR exome

AF:

0.0000680

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000438

Gnomad4 SAS exome

AF:

0.00185

Gnomad4 FIN exome

AF:

0.0000210

Gnomad4 NFE exome

AF:

0.0000208

Gnomad4 OTH exome

AF:

0.000125

GnomAD4 genome

AF:

0.000303

AC:

AN:

151766

Hom.:

Cov.:

AF XY:

0.000364

AC XY:

AN XY:

74172

show subpopulations

Gnomad4 AFR

AF:

0.000459

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.00252

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000306

Hom.:

ExAC

AF:

0.000139

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.245T>C (p.I82T) alteration is located in exon 1 (coding exon 1) of the CDRT15 gene. This alteration results from a T to C substitution at nucleotide position 245, causing the isoleucine (I) at amino acid position 82 to be replaced by a threonine (T). 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

0.11

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.17

DANN

Benign

0.44

DEOGEN2

Benign

0.030

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.00023

LIST_S2

Benign

0.30

M_CAP

Benign

0.0010

MetaRNN

Benign

0.0098

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.1

REVEL

Benign

0.027

Sift

Benign

0.19

Sift4G

Uncertain

0.050

Polyphen

0.0

Vest4

0.034

MVP

0.14

MPC

1.2

ClinPred

0.19

GERP RS

-0.26

Varity_R

0.078

gMVP

0.020

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