chr2-73452739-T-C

Variant names:

• chr2-73452739-T-C
• rs10496192
• NM_001378454.1:c.6212T>C

Variant summary

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

The NM_001378454.1(ALMS1):​c.6212T>C​(p.Ile2071Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,613,212 control chromosomes in the GnomAD database, including 21,161 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. I2071V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1600 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19561 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.124
• Publications: 27 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=9.441972E-4).
• BP6: Variant 2-73452739-T-C is Benign according to our data. Variant chr2-73452739-T-C is described in ClinVar as Benign. ClinVar VariationId is 383769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.176 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	NM_001378454.1	MANE Select	c.6212T>C	p.Ile2071Thr	missense	Exon 8 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.6212T>C	p.Ile2071Thr	missense	Exon 8 of 23	NP_055935.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.6212T>C	p.Ile2071Thr	missense	Exon 8 of 23	ENSP00000482968.1
	ALMS1	ENST00000484298.5	TSL:1	c.6086T>C	p.Ile2029Thr	missense	Exon 7 of 22	ENSP00000478155.1
	ALMS1	ENST00000423048.5	TSL:1	n.1043T>C		non_coding_transcript_exon	Exon 1 of 9	ENSP00000399833.1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20924 AN: 152070 Hom.: 1599 Cov.: 32

Gnomad AFR AF: 0.0811

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.156

GnomAD2 exomes AF: 0.145 AC: 35804 AN: 246918 AF XY: 0.147

Gnomad AFR exome AF: 0.0795

Gnomad AMR exome AF: 0.177

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.00413

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.170

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.161 AC: 234698 AN: 1461024 Hom.: 19561 Cov.: 38 AF XY: 0.161 AC XY: 117148 AN XY: 726836

African (AFR) AF: 0.0794 AC: 2659 AN: 33474

American (AMR) AF: 0.181 AC: 8070 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 3743 AN: 26130

East Asian (EAS) AF: 0.00403 AC: 160 AN: 39674

South Asian (SAS) AF: 0.151 AC: 13013 AN: 86246

European-Finnish (FIN) AF: 0.131 AC: 6941 AN: 52858

Middle Eastern (MID) AF: 0.188 AC: 1087 AN: 5768

European-Non Finnish (NFE) AF: 0.171 AC: 190025 AN: 1111790

Other (OTH) AF: 0.149 AC: 9000 AN: 60382

GnomAD4 genome AF: 0.138 AC: 20938 AN: 152188 Hom.: 1600 Cov.: 32 AF XY: 0.135 AC XY: 10074 AN XY: 74412

African (AFR) AF: 0.0810 AC: 3366 AN: 41538

American (AMR) AF: 0.182 AC: 2773 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 517 AN: 3472

East Asian (EAS) AF: 0.00405 AC: 21 AN: 5188

South Asian (SAS) AF: 0.130 AC: 626 AN: 4814

European-Finnish (FIN) AF: 0.132 AC: 1395 AN: 10604

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11639 AN: 67984

Other (OTH) AF: 0.154 AC: 326 AN: 2112

Alfa AF: 0.155 Hom.: 4517

Bravo AF: 0.140

TwinsUK AF: 0.164 AC: 609

ALSPAC AF: 0.168 AC: 649

ESP6500AA AF: 0.0804 AC: 292

ESP6500EA AF: 0.167 AC: 1356

ExAC AF: 0.142 AC: 17109

Asia WGS AF: 0.0630 AC: 219 AN: 3478

EpiCase AF: 0.174

EpiControl AF: 0.177

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	0.14
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.4
DANN	Benign	0.56
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.00094	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.12
PrimateAI	Benign	0.40	T
Sift4G	Benign	1.0	T
Vest4		0.048
ClinPred		0.0012	T
GERP RS		-5.1
PromoterAI		-0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.018
Mutation Taster		=94/6	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: rs10496192; hg19: chr2-73679866; COSMIC: COSV107272369; COSMIC: COSV107272369;