7-140527401-C-G

Variant names:

• chr7-140527401-C-G
• rs371401607
• NM_015689.5:c.2422G>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.2422G>C​(p.Asp808His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,322 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D808N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DENND2A NM_015689.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.33
• 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, 0.925

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.2422G>C	p.Asp808His	missense	Exon 15 of 20	NP_056504.3	Q9ULE3-1
	DENND2A	NM_001318052.2		c.2422G>C	p.Asp808His	missense	Exon 14 of 19	NP_001304981.1	Q9ULE3-1
	DENND2A	NM_001362678.2		c.2422G>C	p.Asp808His	missense	Exon 15 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.2422G>C	p.Asp808His	missense	Exon 15 of 20	ENSP00000419654.1	Q9ULE3-1
	DENND2A	ENST00000275884.10	TSL:1	c.2422G>C	p.Asp808His	missense	Exon 14 of 19	ENSP00000275884.6	Q9ULE3-1
	DENND2A	ENST00000537639.5	TSL:1	c.2422G>C	p.Asp808His	missense	Exon 13 of 18	ENSP00000442245.1	Q9ULE3-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457322 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724694

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 43950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.00 AC: 0 AN: 85382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110890

Other (OTH) AF: 0.00 AC: 0 AN: 60208

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.75		Gain of catalytic residue at S812 (P = 0.2252)
MVP		0.38
MPC		0.81
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.95
gMVP		0.78
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs371401607; hg19: chr7-140227201;