2-73448097-TCTC-TCTCCTC

Variant names:

• chr2-73448097-T-TCTC
• rs34628045
• NM_001378454.1:c.1574_1576dupCTC

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PM4_Supporting BP6_Very_Strong

The NM_001378454.1(ALMS1):​c.1574_1576dupCTC​(p.Pro525dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L526L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: ALMS1 NM_001378454.1 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0440
• Publications: 18 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

ENSG00000295621 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001378454.1. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 2-73448097-T-TCTC is Benign according to our data. Variant chr2-73448097-T-TCTC is described in ClinVar as Benign. ClinVar VariationId is 221186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1574_1576dupCTC	p.Pro525dup	disruptive_inframe_insertion	Exon 8 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.1574_1576dupCTC	p.Pro525dup	disruptive_inframe_insertion	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.1574_1576dupCTC	p.Pro525dup	disruptive_inframe_insertion	Exon 8 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.1448_1450dupCTC	p.Pro483dup	disruptive_inframe_insertion	Exon 7 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000684548.1		c.1193_1195dupCTC	p.Pro398dup	disruptive_inframe_insertion	Exon 6 of 21	ENSP00000507421.1	A0A804HJA5

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.645 AC: 160831 AN: 249214 AF XY: 0.647

Gnomad AFR exome AF: 0.350

Gnomad AMR exome AF: 0.730

Gnomad ASJ exome AF: 0.630

Gnomad EAS exome AF: 0.779

Gnomad FIN exome AF: 0.627

Gnomad NFE exome AF: 0.636

Gnomad OTH exome AF: 0.653

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.313 Hom.: 2755

Asia WGS AF: 0.711 AC: 2472 AN: 3478

EpiCase AF: 0.646

EpiControl AF: 0.639

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.044

Splicing

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

Other links and lift over

dbSNP: rs34628045; hg19: chr2-73675227; COSMIC: COSV52501590; COSMIC: COSV52501590;