2-73452829-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001378454.1(ALMS1):c.6302C>T(p.Ser2101Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0305 in 1,613,406 control chromosomes in the GnomAD database, including 953 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2101W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.026 ( 81 hom., cov: 33)

Exomes 𝑓: 0.031 ( 872 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.343

Publications

19 publications found

Variant links:

Genes affected

ALMS1 (HGNC:428): (ALMS1 centrosome and basal body associated protein) This gene encodes a protein containing a large tandem-repeat domain as well as additional low complexity regions. The encoded protein functions in microtubule organization, particularly in the formation and maintanance of cilia. Mutations in this gene cause Alstrom syndrome. There is a pseudogene for this gene located adjacent in the same region of chromosome 2. Alternative splice variants have been described but their full length nature has not been determined. [provided by RefSeq, Apr 2014]

ALMS1 Gene-Disease associations (from GenCC):

Alstrom syndrome
Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ALMS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021589994).

BP6

Variant 2-73452829-C-T is Benign according to our data. Variant chr2-73452829-C-T is described in ClinVar as Benign. ClinVar VariationId is 383773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0646 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378454.1. 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
	ALMS1	NM_001378454.1	MANE Select	c.6302C>T	p.Ser2101Leu	missense	Exon 8 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.6302C>T	p.Ser2101Leu	missense	Exon 8 of 23	NP_055935.4	Q8TCU4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.6302C>T	p.Ser2101Leu	missense	Exon 8 of 23	ENSP00000482968.1	Q8TCU4-1
ALMS1	ENST00000484298.5	TSL:1	c.6176C>T	p.Ser2059Leu	missense	Exon 7 of 22	ENSP00000478155.1	A0A087WTU9
ALMS1	ENST00000423048.5	TSL:1	n.1133C>T		non_coding_transcript_exon	Exon 1 of 9	ENSP00000399833.1	H7C1D9

Frequencies

GnomAD3 genomes

AF:

0.0262

AC:

3991

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00633

Gnomad AMI

AF:

0.0989

Gnomad AMR

AF:

0.0342

Gnomad ASJ

AF:

0.0743

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00663

Gnomad FIN

AF:

0.0174

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0375

Gnomad OTH

AF:

0.0354

GnomAD2 exomes

AF:

0.0262

AC:

6495

AN:

247674

AF XY:

0.0267

show subpopulations

Gnomad AFR exome

AF:

0.00527

Gnomad AMR exome

AF:

0.0207

Gnomad ASJ exome

AF:

0.0753

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.0176

Gnomad NFE exome

AF:

0.0366

Gnomad OTH exome

AF:

0.0379

GnomAD4 exome

AF:

0.0310

AC:

45253

AN:

1461192

Hom.:

872

Cov.:

AF XY:

0.0307

AC XY:

22334

AN XY:

726890

show subpopulations

African (AFR)

AF:

0.00720

AC:

241

AN:

33474

American (AMR)

AF:

0.0222

AC:

991

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.0761

AC:

1988

AN:

26126

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39666

South Asian (SAS)

AF:

0.00821

AC:

708

AN:

86242

European-Finnish (FIN)

AF:

0.0185

AC:

982

AN:

53202

Middle Eastern (MID)

AF:

0.0702

AC:

405

AN:

5766

European-Non Finnish (NFE)

AF:

0.0342

AC:

37993

AN:

1111684

Other (OTH)

AF:

0.0322

AC:

1943

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

2419

4837

7256

9674

12093

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1350

2700

4050

5400

6750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0262

AC:

3992

AN:

152214

Hom.:

Cov.:

AF XY:

0.0255

AC XY:

1899

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00633

AC:

263

AN:

41532

American (AMR)

AF:

0.0341

AC:

522

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0743

AC:

258

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00663

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0174

AC:

184

AN:

10590

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0375

AC:

2549

AN:

68012

Other (OTH)

AF:

0.0350

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

210

420

629

839

1049

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0342

Hom.:

351

Bravo

AF:

0.0265

ESP6500AA

AF:

0.00678

AC:

ESP6500EA

AF:

0.0326

AC:

266

ExAC

AF:

0.0255

AC:

3083

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.0435

EpiControl

AF:

0.0425

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Alstrom syndrome (3)

not provided (3)

Cardiovascular phenotype (1)

Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.039

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.1

PhyloP100

0.34

PrimateAI

Benign

0.37

Sift4G

Uncertain

0.0070

Vest4

0.063

ClinPred

0.014

GERP RS

3.4

PromoterAI

-0.0036

Neutral

(source)

Varity_R

0.069

gMVP

0.076

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over