rs6546836

Variant names:

• chr2-73450706-A-G
• rs6546836
• NM_001378454.1:c.4179A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378454.1(ALMS1):​c.4179A>G​(p.Gln1393Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,612,754 control chromosomes in the GnomAD database, including 61,871 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (13508 hom., cov: 31)
  • Exomes 𝑓: 0.24 (48363 hom.)
• Consequence: ALMS1 NM_001378454.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.99
• Publications: 16 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, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-73450706-A-G is Benign according to our data. Variant chr2-73450706-A-G is described in ClinVar as Benign. ClinVar VariationId is 383757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.99 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.691 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.4179A>G	p.Gln1393Gln	synonymous	Exon 8 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.4179A>G	p.Gln1393Gln	synonymous	Exon 8 of 23	NP_055935.4	Q8TCU4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.4179A>G	p.Gln1393Gln	synonymous	Exon 8 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.4053A>G	p.Gln1351Gln	synonymous	Exon 7 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000684548.1		c.3798A>G	p.Gln1266Gln	synonymous	Exon 6 of 21	ENSP00000507421.1	A0A804HJA5

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55126 AN: 150874 Hom.: 13453 Cov.: 31

Gnomad AFR AF: 0.697

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.365

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.00702

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.202

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.324

GnomAD2 exomes AF: 0.259 AC: 64628 AN: 249284 AF XY: 0.243

Gnomad AFR exome AF: 0.713

Gnomad AMR exome AF: 0.403

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.00607

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.236

Gnomad OTH exome AF: 0.237

GnomAD4 exome AF: 0.241 AC: 351815 AN: 1461762 Hom.: 48363 Cov.: 41 AF XY: 0.237 AC XY: 172163 AN XY: 727198

African (AFR) AF: 0.704 AC: 23578 AN: 33468

American (AMR) AF: 0.403 AC: 18018 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 3961 AN: 26132

East Asian (EAS) AF: 0.0122 AC: 484 AN: 39700

South Asian (SAS) AF: 0.167 AC: 14421 AN: 86254

European-Finnish (FIN) AF: 0.232 AC: 12378 AN: 53420

Middle Eastern (MID) AF: 0.239 AC: 1377 AN: 5766

European-Non Finnish (NFE) AF: 0.237 AC: 262980 AN: 1111926

Other (OTH) AF: 0.242 AC: 14618 AN: 60390

GnomAD4 genome AF: 0.366 AC: 55244 AN: 150992 Hom.: 13508 Cov.: 31 AF XY: 0.361 AC XY: 26602 AN XY: 73740

African (AFR) AF: 0.698 AC: 28656 AN: 41070

American (AMR) AF: 0.366 AC: 5545 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 550 AN: 3458

East Asian (EAS) AF: 0.00704 AC: 36 AN: 5114

South Asian (SAS) AF: 0.152 AC: 723 AN: 4756

European-Finnish (FIN) AF: 0.246 AC: 2551 AN: 10372

Middle Eastern (MID) AF: 0.209 AC: 61 AN: 292

European-Non Finnish (NFE) AF: 0.239 AC: 16205 AN: 67768

Other (OTH) AF: 0.321 AC: 673 AN: 2098

Alfa AF: 0.287 Hom.: 12201

Bravo AF: 0.392

Asia WGS AF: 0.119 AC: 414 AN: 3478

EpiCase AF: 0.231

EpiControl AF: 0.236

ClinVar

ClinVar submissions

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
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0080
DANN	Benign	0.22
PhyloP100		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs6546836; hg19: chr2-73677833; COSMIC: COSV52517242; COSMIC: COSV52517242;