chr7-140519639-C-G

Variant names:

• chr7-140519639-C-G
• rs750619110
• NM_015689.5:c.2991G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015689.5(DENND2A):​c.2991G>C​(p.Lys997Asn) 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: DENND2A NM_015689.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.571

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND2A	NM_015689.5	c.2991G>C	p.Lys997Asn	missense_variant	Exon 19 of 20	ENST00000496613.6	NP_056504.3
DENND2A	NM_001318052.2	c.2991G>C	p.Lys997Asn	missense_variant	Exon 18 of 19		NP_001304981.1
DENND2A	NM_001362678.2	c.2991G>C	p.Lys997Asn	missense_variant	Exon 19 of 20		NP_001349607.1
DENND2A	NR_134477.1	n.3078G>C		non_coding_transcript_exon_variant	Exon 17 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND2A	ENST00000496613.6	c.2991G>C	p.Lys997Asn	missense_variant	Exon 19 of 20	2	NM_015689.5	ENSP00000419654.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2991G>C (p.K997N) alteration is located in exon 17 (coding exon 17) of the DENND2A gene. This alteration results from a G to C substitution at nucleotide position 2991, causing the lysine (K) at amino acid position 997 to be replaced by an asparagine (N). 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	Pathogenic	0.95
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.86	.;D;.
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M;M
PhyloP100		0.57
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Benign	0.095
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.65
MutPred		0.38		Loss of methylation at K997 (P = 0.0274);Loss of methylation at K997 (P = 0.0274);Loss of methylation at K997 (P = 0.0274);
MVP		0.23
MPC		0.79
ClinPred		0.98	D
GERP RS		1.0
Varity_R		0.72
gMVP		0.66
Mutation Taster		=76/24	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

Publications

LitVar

Other links and lift over

dbSNP: rs750619110; hg19: chr7-140219439;