7-140522044-C-G

Variant names:

• chr7-140522044-C-G
• rs776812553
• NM_015689.5:c.2722G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015689.5(DENND2A):​c.2722G>C​(p.Val908Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V908M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DENND2A NM_015689.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.43
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015689.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND2A	NM_015689.5	MANE Select	c.2722G>C	p.Val908Leu	missense	Exon 18 of 20	NP_056504.3	Q9ULE3-1
	DENND2A	NM_001318052.2		c.2722G>C	p.Val908Leu	missense	Exon 17 of 19	NP_001304981.1	Q9ULE3-1
	DENND2A	NM_001362678.2		c.2722G>C	p.Val908Leu	missense	Exon 18 of 20	NP_001349607.1	Q9ULE3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND2A	ENST00000496613.6	TSL:2 MANE Select	c.2722G>C	p.Val908Leu	missense	Exon 18 of 20	ENSP00000419654.1	Q9ULE3-1
	DENND2A	ENST00000275884.10	TSL:1	c.2722G>C	p.Val908Leu	missense	Exon 17 of 19	ENSP00000275884.6	Q9ULE3-1
	DENND2A	ENST00000537639.5	TSL:1	c.2722G>C	p.Val908Leu	missense	Exon 16 of 18	ENSP00000442245.1	Q9ULE3-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.4
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.22
Sift	Benign	0.071	T
Sift4G	Benign	0.11	T
Polyphen		0.72	P
Vest4		0.88
MutPred		0.68		Loss of MoRF binding (P = 0.5068)
MVP		0.67
MPC		0.69
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.23
gMVP		0.62
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs776812553; hg19: chr7-140221844;