22-50312579-G-T

Variant names:

• chr22-50312579-G-T
• rs1024580623
• NM_001001794.4:c.1504C>A

Variant summary

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

The NM_001001794.4(DENND6B):​c.1504C>A​(p.His502Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000208 in 1,439,228 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. H502Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DENND6B NM_001001794.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.68
• Publications: 0 publications found

Genes affected

DENND6B (HGNC:32690): (DENN domain containing 6B) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. Predicted to be located in cytosol. Predicted to be active in recycling endosome. [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
DENND6B	NM_001001794.4	c.1504C>A	p.His502Asn	missense_variant	Exon 18 of 20	ENST00000413817.8	NP_001001794.3
DENND6B	XM_011530692.4	c.1666C>A	p.His556Asn	missense_variant	Exon 19 of 21		XP_011528994.1
DENND6B	XM_005261914.5	c.1651C>A	p.His551Asn	missense_variant	Exon 19 of 21		XP_005261971.1
DENND6B	XM_011530693.4	c.1519C>A	p.His507Asn	missense_variant	Exon 18 of 20		XP_011528995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND6B	ENST00000413817.8	c.1504C>A	p.His502Asn	missense_variant	Exon 18 of 20	1	NM_001001794.4	ENSP00000391524.2
DENND6B	ENST00000495607.5	n.2023C>A		non_coding_transcript_exon_variant	Exon 15 of 17	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1439228 Hom.: 0 Cov.: 37 AF XY: 0.00000420 AC XY: 3 AN XY: 714006

African (AFR) AF: 0.00 AC: 0 AN: 33064

American (AMR) AF: 0.00 AC: 0 AN: 41682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25744

East Asian (EAS) AF: 0.00 AC: 0 AN: 38606

South Asian (SAS) AF: 0.00 AC: 0 AN: 83352

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1101640

Other (OTH) AF: 0.00 AC: 0 AN: 59452

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.018
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.084
Sift	Benign	0.039	D
Sift4G	Benign	0.073	T
Polyphen		0.18	B
Vest4		0.65
MutPred		0.56		Loss of disorder (P = 0.0916);
MVP		0.55
MPC		0.13
ClinPred		0.97	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.41
Mutation Taster		=74/26	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: rs1024580623; hg19: chr22-50751008;