1-111188250-C-G

Variant names:

• chr1-111188250-C-G
• rs529531742
• NM_024901.5:c.1220G>C

Variant summary

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

The NM_024901.5(DENND2D):​c.1220G>C​(p.Arg407Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R407I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DENND2D NM_024901.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.974
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024901.5. 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
	DENND2D	NM_024901.5	MANE Select	c.1220G>C	p.Arg407Thr	missense	Exon 11 of 12	NP_079177.2
	DENND2D	NM_001271833.2		c.1211G>C	p.Arg404Thr	missense	Exon 11 of 12	NP_001258762.1	Q9H6A0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND2D	ENST00000357640.9	TSL:1 MANE Select	c.1220G>C	p.Arg407Thr	missense	Exon 11 of 12	ENSP00000350266.4	Q9H6A0-1
	DENND2D	ENST00000369752.5	TSL:2	c.1211G>C	p.Arg404Thr	missense	Exon 11 of 12	ENSP00000358767.5	Q9H6A0-2
	DENND2D	ENST00000900292.1		c.1142G>C	p.Arg381Thr	missense	Exon 10 of 11	ENSP00000570351.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.058	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.97
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.13
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.025	D
Polyphen		0.84	P
Vest4		0.57
MutPred		0.66		Loss of MoRF binding (P = 0.0238)
MVP		0.56
MPC		1.1
ClinPred		0.72	D
GERP RS		4.8
Varity_R		0.16
gMVP		0.50
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs529531742; hg19: chr1-111730872;