1-111188734-T-G

Position:

• chr1-111188734-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024901.5(DENND2D):​c.1067A>C​(p.Asp356Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DENND2D NM_024901.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.169

Genes affected

DENND2D (HGNC:26192): (DENN domain containing 2D) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DENND2D (HGNC:):

ACMG classification

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=0.033889055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND2D	NM_024901.5	c.1067A>C	p.Asp356Ala	missense_variant	10/12	ENST00000357640.9	NP_079177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND2D	ENST00000357640.9	c.1067A>C	p.Asp356Ala	missense_variant	10/12	1	NM_024901.5	ENSP00000350266.4
DENND2D	ENST00000369752.5	c.1058A>C	p.Asp353Ala	missense_variant	10/12	2		ENSP00000358767.5
DENND2D	ENST00000468692.1	n.170A>C		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2024

The c.1067A>C (p.D356A) alteration is located in exon 10 (coding exon 10) of the DENND2D gene. This alteration results from a A to C substitution at nucleotide position 1067, causing the aspartic acid (D) at amino acid position 356 to be replaced by an alanine (A). 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	0.064
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	3.2
DANN	Benign	0.69
DEOGEN2	Benign	0.024	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.15	T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.034	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.95	N;N
REVEL	Benign	0.023
Sift	Benign	0.30	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.0020	B;B
Vest4		0.15
MutPred		0.33		Loss of disorder (P = 0.0829);.;
MVP		0.17
MPC		0.38
ClinPred		0.10	T
GERP RS		-3.2
Varity_R		0.063
gMVP		0.29

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: chr1-111731356;