7-140522007-G-C

Position:

• chr7-140522007-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015689.5(DENND2A):​c.2759C>G​(p.Ser920Trp) 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. 14/21 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: 33)
• Consequence: DENND2A NM_015689.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10

Genes affected

DENND2A (HGNC:22212): (DENN domain containing 2A) Enables guanyl-nucleotide exchange factor activity. Involved in retrograde transport, endosome to Golgi. Located in actin cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.098881334).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND2A	NM_015689.5	c.2759C>G	p.Ser920Trp	missense_variant	18/20	ENST00000496613.6	NP_056504.3
DENND2A	NM_001318052.2	c.2759C>G	p.Ser920Trp	missense_variant	17/19		NP_001304981.1
DENND2A	NM_001362678.2	c.2759C>G	p.Ser920Trp	missense_variant	18/20		NP_001349607.1
DENND2A	NR_134477.1	n.2846C>G		non_coding_transcript_exon_variant	16/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND2A	ENST00000496613.6	c.2759C>G	p.Ser920Trp	missense_variant	18/20	2	NM_015689.5	ENSP00000419654.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Dec 03, 2024

The c.2759C>G (p.S920W) alteration is located in exon 16 (coding exon 16) of the DENND2A gene. This alteration results from a C to G substitution at nucleotide position 2759, causing the serine (S) at amino acid position 920 to be replaced by a tryptophan (W). 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	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.8
DANN	Benign	0.95
DEOGEN2	Benign	0.029	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.92	.;D;.
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.099	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.079
Sift	Benign	0.041	D;D;D
Sift4G	Uncertain	0.040	D;D;D
Polyphen		0.0040	B;B;B
Vest4		0.36
MutPred		0.52		Loss of disorder (P = 0.0023);Loss of disorder (P = 0.0023);Loss of disorder (P = 0.0023);
MVP		0.068
MPC		0.78
ClinPred		0.71	D
GERP RS		1.8
Varity_R		0.058
gMVP		0.30

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: chr7-140221807;