1-197595326-G-A

Variant names:

• chr1-197595326-G-A
• rs202173941
• NM_001195215.2:c.929C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001195215.2(DENND1B):​c.929C>T​(p.Ala310Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000862 in 1,612,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: DENND1B NM_001195215.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.20
• Publications: 3 publications found

Genes affected

DENND1B (HGNC:28404): (DENN domain containing 1B) Clathrin (see MIM 118955)-mediated endocytosis is a major mechanism for internalization of proteins and lipids. Members of the connecdenn family, such as DENND1B, function as guanine nucleotide exchange factors (GEFs) for the early endosomal small GTPase RAB35 (MIM 604199) and bind to clathrin and clathrin adaptor protein-2 (AP2; see MIM 601024). Thus, connecdenns link RAB35 activation with the clathrin machinery (Marat and McPherson, 2010 [PubMed 20154091]).[supplied by OMIM, Nov 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017838806).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195215.2. 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
	DENND1B	NM_001195215.2	MANE Select	c.929C>T	p.Ala310Val	missense	Exon 14 of 23	NP_001182144.1	Q6P3S1-1
	DENND1B	NM_144977.5		c.929C>T	p.Ala310Val	missense	Exon 14 of 16	NP_659414.2	Q6P3S1-5
	DENND1B	NM_001300858.2		c.839C>T	p.Ala280Val	missense	Exon 14 of 16	NP_001287787.1	Q6P3S1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND1B	ENST00000620048.6	TSL:5 MANE Select	c.929C>T	p.Ala310Val	missense	Exon 14 of 23	ENSP00000479816.1	Q6P3S1-1
	DENND1B	ENST00000367396.7	TSL:1	c.929C>T	p.Ala310Val	missense	Exon 14 of 16	ENSP00000356366.3	Q6P3S1-5
	DENND1B	ENST00000235453.8	TSL:1	c.839C>T	p.Ala280Val	missense	Exon 14 of 16	ENSP00000235453.4	Q6P3S1-4

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 151962 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000157 AC: 39 AN: 248228 AF XY: 0.000163

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00330

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000829 AC: 121 AN: 1460240 Hom.: 0 Cov.: 30 AF XY: 0.0000743 AC XY: 54 AN XY: 726440

African (AFR) AF: 0.00 AC: 0 AN: 33384

American (AMR) AF: 0.00 AC: 0 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00365 AC: 95 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1110960

Other (OTH) AF: 0.000199 AC: 12 AN: 60318

GnomAD4 genome AF: 0.000118 AC: 18 AN: 151962 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74228

African (AFR) AF: 0.00 AC: 0 AN: 41376

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000315 Hom.: 0

Bravo AF: 0.0000945

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000993 AC: 12

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	25
DANN	Benign	0.96
Eigen	Benign	0.014
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.047
Sift	Benign	0.51	T
Sift4G	Benign	0.13	T
Polyphen		0.0080	B
Vest4		0.44
MutPred		0.34		Loss of disorder (P = 0.086)
MVP		0.093
MPC		0.059
ClinPred		0.10	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.40
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs202173941; hg19: chr1-197564456; COSMIC: COSV104581354;