rs6724782

Variant names:

• chr2-73452863-T-A
• rs6724782
• NM_001378454.1:c.6336T>A

Your query was ambiguous. Multiple possible variants found:

• chr2-73452863-T-A
• chr2-73452863-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015120.4(ALMS1):​c.6336T>A​(p.Ser2112Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,613,406 control chromosomes in the GnomAD database, including 66,846 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S2112S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.39 (15917 hom., cov: 32)
  • Exomes 𝑓: 0.24 (50929 hom.)
• Consequence: ALMS1 NM_015120.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0800
• Publications: 35 publications found

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 Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Orphanet, Genomics England PanelApp

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=9.135518E-7).
• BP6: Variant 2-73452863-T-A is Benign according to our data. Variant chr2-73452863-T-A is described in ClinVar as Benign. ClinVar VariationId is 383759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015120.4. 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.6336T>A	p.Ser2112Arg	missense	Exon 8 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.6336T>A	p.Ser2112Arg	missense	Exon 8 of 23	NP_055935.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.6336T>A	p.Ser2112Arg	missense	Exon 8 of 23	ENSP00000482968.1
	ALMS1	ENST00000484298.5	TSL:1	c.6210T>A	p.Ser2070Arg	missense	Exon 7 of 22	ENSP00000478155.1
	ALMS1	ENST00000423048.5	TSL:1	n.1167T>A		non_coding_transcript_exon	Exon 1 of 9	ENSP00000399833.1

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58803 AN: 151986 Hom.: 15854 Cov.: 32

Gnomad AFR AF: 0.768

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.00714

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.340

GnomAD2 exomes AF: 0.267 AC: 66163 AN: 248136 AF XY: 0.249

Gnomad AFR exome AF: 0.784

Gnomad AMR exome AF: 0.408

Gnomad ASJ exome AF: 0.204

Gnomad EAS exome AF: 0.00608

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.244

GnomAD4 exome AF: 0.244 AC: 356982 AN: 1461302 Hom.: 50929 Cov.: 38 AF XY: 0.240 AC XY: 174574 AN XY: 726966

African (AFR) AF: 0.781 AC: 26153 AN: 33476

American (AMR) AF: 0.409 AC: 18247 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 5322 AN: 26128

East Asian (EAS) AF: 0.0122 AC: 485 AN: 39668

South Asian (SAS) AF: 0.167 AC: 14429 AN: 86242

European-Finnish (FIN) AF: 0.232 AC: 12330 AN: 53244

Middle Eastern (MID) AF: 0.244 AC: 1407 AN: 5768

European-Non Finnish (NFE) AF: 0.237 AC: 263456 AN: 1111736

Other (OTH) AF: 0.251 AC: 15153 AN: 60380

GnomAD4 genome AF: 0.387 AC: 58929 AN: 152104 Hom.: 15917 Cov.: 32 AF XY: 0.380 AC XY: 28281 AN XY: 74336

African (AFR) AF: 0.768 AC: 31883 AN: 41506

American (AMR) AF: 0.373 AC: 5703 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 710 AN: 3472

East Asian (EAS) AF: 0.00716 AC: 37 AN: 5170

South Asian (SAS) AF: 0.151 AC: 728 AN: 4820

European-Finnish (FIN) AF: 0.243 AC: 2574 AN: 10572

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.239 AC: 16276 AN: 67964

Other (OTH) AF: 0.336 AC: 709 AN: 2110

Alfa AF: 0.274 Hom.: 2353

Bravo AF: 0.416

TwinsUK AF: 0.229 AC: 850

ALSPAC AF: 0.234 AC: 901

ESP6500AA AF: 0.740 AC: 2748

ESP6500EA AF: 0.239 AC: 1956

ExAC AF: 0.269 AC: 32471

Asia WGS AF: 0.124 AC: 431 AN: 3478

EpiCase AF: 0.233

EpiControl AF: 0.237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Alstrom syndrome (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.12
DANN	Benign	0.66
DEOGEN2	Benign	0.0074	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	9.1e-7	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.080
PrimateAI	Benign	0.26	T
Sift4G	Benign	0.63	T
Vest4		0.037
ClinPred		0.0043	T
GERP RS		-5.1
PromoterAI		0.0020	Neutral
Varity_R		0.026
gMVP		0.019
Mutation Taster		=100/0	polymorphism (auto)

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: rs6724782; hg19: chr2-73679990; COSMIC: COSV52517254; COSMIC: COSV52517254;