2-169497628-G-A

Position:

chr2-169497628-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_152384.3(BBS5):c.620G>A(p.Arg207His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00785 in 1,576,430 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R207C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0061 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0080 ( 86 hom. )

Consequence

BBS5
NM_152384.3 missense, splice_region

Scores

Splicing: ADA: 0.9811

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 9.18

Variant links:

Genes affected

BBS5 (HGNC:970): (Bardet-Biedl syndrome 5) This gene encodes a protein that has been directly linked to Bardet-Biedl syndrome. The primary features of this syndrome include retinal dystrophy, obesity, polydactyly, renal abnormalities and learning disabilities. Experimentation in non-human eukaryotes suggests that this gene is expressed in ciliated cells and that it is required for the formation of cilia. Alternate transcriptional splice variants have been observed but have not been fully characterized. [provided by RefSeq, Jul 2008]

BBS5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 2-169497628-G-A is Benign according to our data. Variant chr2-169497628-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 96499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169497628-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00612 (931/152124) while in subpopulation NFE AF= 0.00859 (584/67974). AF 95% confidence interval is 0.00801. There are 1 homozygotes in gnomad4. There are 459 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 86 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS5	NM_152384.3 linkuse as main transcript	c.620G>A	p.Arg207His	missense_variant, splice_region_variant	8/12	ENST00000295240.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS5	ENST00000295240.8 linkuse as main transcript	c.620G>A	p.Arg207His	missense_variant, splice_region_variant	8/12	1	NM_152384.3	P1	Q8N3I7-1
BBS5	ENST00000392663.6 linkuse as main transcript	c.619-1858G>A		intron_variant		1			Q8N3I7-2
BBS5	ENST00000443151.1 linkuse as main transcript	c.*342G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	6/6	5

Frequencies

GnomAD3 genomes

AF:

0.00612

AC:

931

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00289

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.0135

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00859

Gnomad OTH

AF:

0.00622

GnomAD3 exomes

AF:

0.00656

AC:

1643

AN:

250580

Hom.:

AF XY:

0.00681

AC XY:

923

AN XY:

135514

show subpopulations

Gnomad AFR exome

AF:

0.00242

Gnomad AMR exome

AF:

0.00293

Gnomad ASJ exome

AF:

0.00348

Gnomad EAS exome

AF:

0.00114

Gnomad SAS exome

AF:

0.00612

Gnomad FIN exome

AF:

0.0105

Gnomad NFE exome

AF:

0.00884

Gnomad OTH exome

AF:

0.00508

GnomAD4 exome

AF:

0.00803

AC:

11437

AN:

1424306

Hom.:

Cov.:

AF XY:

0.00798

AC XY:

5667

AN XY:

710514

show subpopulations

Gnomad4 AFR exome

AF:

0.00147

Gnomad4 AMR exome

AF:

0.00300

Gnomad4 ASJ exome

AF:

0.00298

Gnomad4 EAS exome

AF:

0.00429

Gnomad4 SAS exome

AF:

0.00626

Gnomad4 FIN exome

AF:

0.0104

Gnomad4 NFE exome

AF:

0.00886

Gnomad4 OTH exome

AF:

0.00573

GnomAD4 genome

AF:

0.00612

AC:

931

AN:

152124

Hom.:

Cov.:

AF XY:

0.00617

AC XY:

459

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00222

Gnomad4 AMR

AF:

0.00334

Gnomad4 ASJ

AF:

0.00289

Gnomad4 EAS

AF:

0.000965

Gnomad4 SAS

AF:

0.00643

Gnomad4 FIN

AF:

0.0135

Gnomad4 NFE

AF:

0.00859

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00698

Hom.:

Bravo

AF:

0.00512

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00341

AC:

ESP6500EA

AF:

0.00828

AC:

ExAC

AF:

0.00640

AC:

777

Asia WGS

AF:

0.00289

AC:

AN:

3472

EpiCase

AF:

0.00765

EpiControl

AF:

0.00735

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 25, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: BBS5 c.620G>A (p.Arg207His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0066 in 250580 control chromosomes in the gnomAD database, including 11 homozygotes. The observed variant frequency is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in BBS5 causing Bardet-Biedl Syndrome phenotype (0.00062), strongly suggesting that the variant is benign. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	BBS5: BP4, BS2 -

Bardet-Biedl syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

T;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.4

L;.

MutationTaster

Benign

1.0

D;D;D

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.23

Sift

Benign

0.12

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.83

P;.

Vest4

0.56

MVP

0.86

MPC

0.61

ClinPred

0.012

GERP RS

5.7

Varity_R

0.16

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.84

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over