10-277520-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_014974.3(DIP2C):c.4476A>C(p.Glu1492Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DIP2C NM_014974.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0380

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DIP2C

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIP2C	NM_014974.3	c.4476A>C	p.Glu1492Asp	missense_variant	37/37	ENST00000280886.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIP2C	ENST00000280886.12	c.4476A>C	p.Glu1492Asp	missense_variant	37/37	1	NM_014974.3	P1
DIP2C	ENST00000634311.1	c.4674A>C	p.Glu1558Asp	missense_variant	39/39	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with DIP2C-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with aspartic acid at codon 1492 of the DIP2C protein (p.Glu1492Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	14
Dann	Uncertain	0.98
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.76	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.61, 0.60
MutPred		0.33		.;Gain of relative solvent accessibility (P = 0.1571);.;
MVP		0.23
MPC		1.7
ClinPred		0.90	D
GERP RS		-0.20
Varity_R		0.26
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-323460;