Genetic Variant NM_014974.3:c.602T>C (chr10-422826-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_014974.3(DIP2C):c.602T>C(p.Ile201Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,458,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

DIP2C
NM_014974.3 missense, splice_region

Scores

Splicing: ADA: 0.4623

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.65

Variant links:

Genes affected

DIP2C (HGNC:29150): (disco interacting protein 2 homolog C) This gene encodes a member of the disco-interacting protein homolog 2 family. The protein shares strong similarity with a Drosophila protein which interacts with the transcription factor disco and is expressed in the nervous system. [provided by RefSeq, Oct 2008]

DIP2C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1891174).

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIP2C	NM_014974.3 link	c.602T>C	p.Ile201Thr	missense_variant, splice_region_variant	Exon 5 of 37	ENST00000280886.12	NP_055789.1	Q9Y2E4-1Q86XV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIP2C	ENST00000280886.12 link	c.602T>C	p.Ile201Thr	missense_variant, splice_region_variant	Exon 5 of 37	1	NM_014974.3	ENSP00000280886.6		Q9Y2E4-1
DIP2C	ENST00000634311.1 link	c.770T>C	p.Ile257Thr	missense_variant, splice_region_variant	Exon 6 of 39	5		ENSP00000489203.1		A0A0U1RQW6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249120

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134632

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1458998

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725828

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000670

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Apr 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.602T>C (p.I201T) alteration is located in exon 5 (coding exon 5) of the DIP2C gene. This alteration results from a T to C substitution at nucleotide position 602, causing the isoleucine (I) at amino acid position 201 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

0.093

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.053

.;T;T

Eigen

Benign

-0.0071

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.0029

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

.;L;.

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.2

.;N;.

REVEL

Benign

0.11

Sift

Benign

0.085

.;T;.

Sift4G

Benign

0.22

T;T;T

Polyphen

0.039

.;B;.

Vest4

0.70, 0.71

MutPred

0.26

.;Gain of phosphorylation at I201 (P = 0.0364);.;

MVP

0.043

MPC

0.96

ClinPred

0.45

GERP RS

5.4

Varity_R

0.10

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.46

dbscSNV1_RF

Benign

0.51

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