1-197595260-C-T

Variant names:

• chr1-197595260-C-T
• rs771538170
• NM_001195215.2:c.995G>A

Variant summary

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

The NM_001195215.2(DENND1B):​c.995G>A​(p.Arg332Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R332T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DENND1B NM_001195215.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.82
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.995G>A	p.Arg332Lys	missense	Exon 14 of 23	NP_001182144.1	Q6P3S1-1
	DENND1B	NM_144977.5		c.995G>A	p.Arg332Lys	missense	Exon 14 of 16	NP_659414.2	Q6P3S1-5
	DENND1B	NM_001300858.2		c.905G>A	p.Arg302Lys	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.995G>A	p.Arg332Lys	missense	Exon 14 of 23	ENSP00000479816.1	Q6P3S1-1
	DENND1B	ENST00000367396.7	TSL:1	c.995G>A	p.Arg332Lys	missense	Exon 14 of 16	ENSP00000356366.3	Q6P3S1-5
	DENND1B	ENST00000235453.8	TSL:1	c.905G>A	p.Arg302Lys	missense	Exon 14 of 16	ENSP00000235453.4	Q6P3S1-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Benign	0.89
Eigen	Benign	-0.064
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.19
Sift	Benign	0.81	T
Sift4G	Benign	0.97	T
Polyphen		0.047	B
Vest4		0.81
MutPred		0.65		Gain of ubiquitination at R332 (P = 0.0428)
MVP		0.49
MPC		0.27
ClinPred		0.79	D
GERP RS		6.1
Varity_R		0.89
gMVP		0.66
Mutation Taster		=31/69	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: rs771538170; hg19: chr1-197564390;