chr1-197617670-C-T

Variant names:

• chr1-197617670-C-T
• rs77063931
• NM_001195215.2:c.762G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001195215.2(DENND1B):​c.762G>A​(p.Leu254Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,606,722 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (76 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (75 hom.)
• Consequence: DENND1B NM_001195215.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.01
• Publications: 1 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 1-197617670-C-T is Benign according to our data. Variant chr1-197617670-C-T is described in ClinVar as Benign. ClinVar VariationId is 781797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0583 is higher than 0.05.

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.762G>A	p.Leu254Leu	synonymous	Exon 11 of 23	NP_001182144.1	Q6P3S1-1
	DENND1B	NM_144977.5		c.762G>A	p.Leu254Leu	synonymous	Exon 11 of 16	NP_659414.2	Q6P3S1-5
	DENND1B	NM_001300858.2		c.672G>A	p.Leu224Leu	synonymous	Exon 11 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.762G>A	p.Leu254Leu	synonymous	Exon 11 of 23	ENSP00000479816.1	Q6P3S1-1
	DENND1B	ENST00000367396.7	TSL:1	c.762G>A	p.Leu254Leu	synonymous	Exon 11 of 16	ENSP00000356366.3	Q6P3S1-5
	DENND1B	ENST00000235453.8	TSL:1	c.672G>A	p.Leu224Leu	synonymous	Exon 11 of 16	ENSP00000235453.4	Q6P3S1-4

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2659 AN: 151152 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.0603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00203

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000400

Gnomad OTH AF: 0.0149

GnomAD2 exomes AF: 0.00449 AC: 1111 AN: 247332 AF XY: 0.00348

Gnomad AFR exome AF: 0.0622

Gnomad AMR exome AF: 0.00271

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000375

Gnomad OTH exome AF: 0.00201

GnomAD4 exome AF: 0.00191 AC: 2784 AN: 1455452 Hom.: 75 Cov.: 30 AF XY: 0.00168 AC XY: 1215 AN XY: 724186

African (AFR) AF: 0.0613 AC: 2027 AN: 33052

American (AMR) AF: 0.00326 AC: 145 AN: 44470

Ashkenazi Jewish (ASJ) AF: 0.00108 AC: 28 AN: 25844

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.0000930 AC: 8 AN: 86012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00560 AC: 32 AN: 5714

European-Non Finnish (NFE) AF: 0.000244 AC: 270 AN: 1107524

Other (OTH) AF: 0.00457 AC: 274 AN: 59938

GnomAD4 genome AF: 0.0176 AC: 2664 AN: 151270 Hom.: 76 Cov.: 32 AF XY: 0.0173 AC XY: 1280 AN XY: 73918

African (AFR) AF: 0.0602 AC: 2494 AN: 41404

American (AMR) AF: 0.00674 AC: 102 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 7 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000400 AC: 27 AN: 67416

Other (OTH) AF: 0.0148 AC: 31 AN: 2098

Alfa AF: 0.00756 Hom.: 23

Bravo AF: 0.0197

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000110

EpiControl AF: 0.000774

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	11
DANN	Benign	0.70
PhyloP100		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs77063931; hg19: chr1-197586800;