chr22-50314614-G-T

Variant names:

• chr22-50314614-G-T
• rs370513147
• NM_001001794.4:c.968C>A

Variant summary

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

The NM_001001794.4(DENND6B):​c.968C>A​(p.Thr323Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,410,326 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. T323M) 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: 7.24
• Publications: 1 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]

ENSG00000227484 (HGNC:):

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.968C>A	p.Thr323Lys	missense_variant	Exon 11 of 20	ENST00000413817.8	NP_001001794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND6B	ENST00000413817.8	c.968C>A	p.Thr323Lys	missense_variant	Exon 11 of 20	1	NM_001001794.4	ENSP00000391524.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000174 AC: 3 AN: 171936 AF XY: 0.0000327

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000210

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1410326 Hom.: 0 Cov.: 33 AF XY: 0.00000431 AC XY: 3 AN XY: 696840

African (AFR) AF: 0.00 AC: 0 AN: 32108

American (AMR) AF: 0.0000273 AC: 1 AN: 36600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25334

East Asian (EAS) AF: 0.0000273 AC: 1 AN: 36574

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 80132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085856

Other (OTH) AF: 0.00 AC: 0 AN: 58626

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.2
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.70
Sift	Benign	0.11	T
Sift4G	Benign	0.099	T
Polyphen		1.0	D
Vest4		0.59
MutPred		0.58		Gain of solvent accessibility (P = 0.0012);
MVP		0.50
MPC		0.48
ClinPred		0.87	D
GERP RS		3.8
Varity_R		0.45
gMVP		0.63
Mutation Taster		=43/57	disease causing

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: rs370513147; hg19: chr22-50753043;