7-140601931-G-T

Position:

• chr7-140601931-G-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND2A	NM_015689.5	c.467C>A	p.Pro156His	missense_variant	3/20	ENST00000496613.6	NP_056504.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND2A	ENST00000496613.6	c.467C>A	p.Pro156His	missense_variant	3/20	2	NM_015689.5	ENSP00000419654.1

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

GnomAD3 exomes AF: 0.955 AC: 238359 AN: 249466 Hom.: 113965 AF XY: 0.954 AC XY: 129165 AN XY: 135344

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 SAS exome AF: 0.978

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

Gnomad4 AFR exome AF: 0.990

Gnomad4 AMR exome AF: 0.971

Gnomad4 ASJ exome AF: 0.962

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.976

Gnomad4 FIN exome AF: 0.932

Gnomad4 NFE exome AF: 0.938

Gnomad4 OTH exome AF: 0.950

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

Gnomad4 AFR AF: 0.988

Gnomad4 AMR AF: 0.961

Gnomad4 ASJ AF: 0.966

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.982

Gnomad4 FIN AF: 0.933

Gnomad4 NFE AF: 0.935

Gnomad4 OTH AF: 0.952

Alfa AF: 0.941 Hom.: 172309

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 v4.3

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;T;T;.;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.058	.;T;.;T;T
MetaRNN	Benign	5.4e-7	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N;N;N;N;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.9	N;N;N;N;N
REVEL	Benign	0.028
Sift	Benign	0.32	T;T;T;T;T
Sift4G	Benign	0.32	T;T;T;T;.
Polyphen		0.0	B;B;B;B;.
Vest4		0.034
MPC		0.22
ClinPred		0.015	T
GERP RS		2.8
Varity_R		0.048
gMVP		0.11

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: rs269243; hg19: chr7-140301731;