7-140601931-G-T

Variant names:

• chr7-140601931-G-T
• rs269243
• NM_015689.5:c.467C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015689.5(DENND2A):​c.467C>A​(p.Pro156His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.946 in 1,614,106 control chromosomes in the GnomAD database, including 722,509 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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: 𝑓 0.96 (69661 hom., cov: 32)
  • Exomes 𝑓: 0.94 (652848 hom.)
• Consequence: DENND2A NM_015689.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.00
• Publications: 24 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.422644E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.98 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND2A	NM_015689.5	MANE Select	c.467C>A	p.Pro156His	missense	Exon 3 of 20	NP_056504.3
	DENND2A	NM_001318052.2		c.467C>A	p.Pro156His	missense	Exon 2 of 19	NP_001304981.1
	DENND2A	NM_001362678.2		c.467C>A	p.Pro156His	missense	Exon 3 of 20	NP_001349607.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND2A	ENST00000496613.6	TSL:2 MANE Select	c.467C>A	p.Pro156His	missense	Exon 3 of 20	ENSP00000419654.1
	DENND2A	ENST00000275884.10	TSL:1	c.467C>A	p.Pro156His	missense	Exon 2 of 19	ENSP00000275884.6
	DENND2A	ENST00000537639.5	TSL:1	c.467C>A	p.Pro156His	missense	Exon 1 of 18	ENSP00000442245.1

Frequencies

GnomAD3 genomes AF: 0.956 AC: 145448 AN: 152096 Hom.: 69597 Cov.: 32

Gnomad AFR AF: 0.988

Gnomad AMI AF: 0.859

Gnomad AMR AF: 0.961

Gnomad ASJ AF: 0.966

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.982

Gnomad FIN AF: 0.933

Gnomad MID AF: 0.949

Gnomad NFE AF: 0.935

Gnomad OTH AF: 0.951

GnomAD2 exomes AF: 0.955 AC: 238359 AN: 249466 AF XY: 0.954

Gnomad AFR exome AF: 0.990

Gnomad AMR exome AF: 0.973

Gnomad ASJ exome AF: 0.963

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.934

Gnomad NFE exome AF: 0.936

Gnomad OTH exome AF: 0.949

GnomAD4 exome AF: 0.945 AC: 1381260 AN: 1461892 Hom.: 652848 Cov.: 97 AF XY: 0.945 AC XY: 687229 AN XY: 727248

African (AFR) AF: 0.990 AC: 33154 AN: 33480

American (AMR) AF: 0.971 AC: 43440 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.962 AC: 25138 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39699 AN: 39700

South Asian (SAS) AF: 0.976 AC: 84217 AN: 86258

European-Finnish (FIN) AF: 0.932 AC: 49782 AN: 53420

Middle Eastern (MID) AF: 0.916 AC: 5285 AN: 5768

European-Non Finnish (NFE) AF: 0.938 AC: 1043176 AN: 1112010

Other (OTH) AF: 0.950 AC: 57369 AN: 60396

GnomAD4 genome AF: 0.956 AC: 145571 AN: 152214 Hom.: 69661 Cov.: 32 AF XY: 0.957 AC XY: 71221 AN XY: 74412

African (AFR) AF: 0.988 AC: 41053 AN: 41548

American (AMR) AF: 0.961 AC: 14690 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.966 AC: 3352 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5148 AN: 5148

South Asian (SAS) AF: 0.982 AC: 4735 AN: 4820

European-Finnish (FIN) AF: 0.933 AC: 9902 AN: 10612

Middle Eastern (MID) AF: 0.952 AC: 280 AN: 294

European-Non Finnish (NFE) AF: 0.935 AC: 63616 AN: 68012

Other (OTH) AF: 0.952 AC: 2013 AN: 2114

Alfa AF: 0.944 Hom.: 248566

Bravo AF: 0.961

TwinsUK AF: 0.945 AC: 3505

ALSPAC AF: 0.941 AC: 3627

ESP6500AA AF: 0.990 AC: 3965

ESP6500EA AF: 0.936 AC: 7797

ExAC AF: 0.955 AC: 115406

Asia WGS AF: 0.991 AC: 3446 AN: 3478

EpiCase AF: 0.938

EpiControl AF: 0.940

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.0079	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.058	T
MetaRNN	Benign	5.4e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N
PhyloP100		2.0
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.028
Sift	Benign	0.32	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.034
MPC		0.22
ClinPred		0.015	T
GERP RS		2.8
Varity_R		0.048
gMVP		0.11
Mutation Taster		=100/0	polymorphism (auto)

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: rs269243; hg19: chr7-140301731; COSMIC: COSV107300867; COSMIC: COSV107300867;