1-197607080-C-G

Variant names:

• chr1-197607080-C-G
• rs1418136561
• NM_001195215.2:c.914G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001195215.2(DENND1B):​c.914G>C​(p.Ser305Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DENND1B NM_001195215.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.35
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.098582804).

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.914G>C	p.Ser305Thr	missense	Exon 13 of 23	NP_001182144.1	Q6P3S1-1
	DENND1B	NM_144977.5		c.914G>C	p.Ser305Thr	missense	Exon 13 of 16	NP_659414.2	Q6P3S1-5
	DENND1B	NM_001300858.2		c.824G>C	p.Ser275Thr	missense	Exon 13 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.914G>C	p.Ser305Thr	missense	Exon 13 of 23	ENSP00000479816.1	Q6P3S1-1
	DENND1B	ENST00000367396.7	TSL:1	c.914G>C	p.Ser305Thr	missense	Exon 13 of 16	ENSP00000356366.3	Q6P3S1-5
	DENND1B	ENST00000235453.8	TSL:1	c.824G>C	p.Ser275Thr	missense	Exon 13 of 16	ENSP00000235453.4	Q6P3S1-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000407 AC: 1 AN: 245470 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452494 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 722712

African (AFR) AF: 0.00 AC: 0 AN: 33028

American (AMR) AF: 0.00 AC: 0 AN: 44324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25794

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39454

South Asian (SAS) AF: 0.00 AC: 0 AN: 85660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105650

Other (OTH) AF: 0.00 AC: 0 AN: 59818

GnomAD4 genome Cov.: 32

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	0.082
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Benign	0.59
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.4
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.032
Sift	Benign	0.54	T
Sift4G	Benign	0.32	T
Polyphen		0.0030	B
Vest4		0.11
MutPred		0.26		Loss of disorder (P = 0.0742)
MVP		0.17
MPC		0.042
ClinPred		0.15	T
GERP RS		4.3
Varity_R		0.26
gMVP		0.21
Mutation Taster		=80/20	polymorphism

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: rs1418136561; hg19: chr1-197576210;