rs10199680

Variant names:

• chr2-73534815-C-T
• rs10199680
• NM_001378454.1:c.9782-9C>T

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.9782-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00639 in 1,612,400 control chromosomes in the GnomAD database, including 556 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (292 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (264 hom.)
• Consequence: ALMS1 NM_001378454.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.183
• Publications: 1 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 (BayesDel_noAF=-0.77).
• BP6: Variant 2-73534815-C-T is Benign according to our data. Variant chr2-73534815-C-T is described in ClinVar as Benign. ClinVar VariationId is 387349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 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.9782-9C>T		intron	N/A	NP_001365383.1
	ALMS1	NM_015120.4		c.9782-9C>T		intron	N/A	NP_055935.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.9782-9C>T		intron	N/A	ENSP00000482968.1
	ALMS1	ENST00000484298.5	TSL:1	c.9656-9C>T		intron	N/A	ENSP00000478155.1
	ALMS1	ENST00000423048.5	TSL:1	n.*201-9C>T		intron	N/A	ENSP00000399833.1

Frequencies

GnomAD3 genomes AF: 0.0336 AC: 5110 AN: 152034 Hom.: 287 Cov.: 33

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.0259

GnomAD2 exomes AF: 0.00869 AC: 2165 AN: 249192 AF XY: 0.00621

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.00519

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000531

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00353 AC: 5152 AN: 1460248 Hom.: 264 Cov.: 31 AF XY: 0.00303 AC XY: 2201 AN XY: 726562

African (AFR) AF: 0.120 AC: 4018 AN: 33358

American (AMR) AF: 0.00611 AC: 273 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00677 AC: 39 AN: 5762

European-Non Finnish (NFE) AF: 0.000319 AC: 354 AN: 1110794

Other (OTH) AF: 0.00740 AC: 446 AN: 60310

GnomAD4 genome AF: 0.0338 AC: 5144 AN: 152152 Hom.: 292 Cov.: 33 AF XY: 0.0329 AC XY: 2447 AN XY: 74382

African (AFR) AF: 0.117 AC: 4838 AN: 41490

American (AMR) AF: 0.0130 AC: 199 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000618 AC: 42 AN: 67982

Other (OTH) AF: 0.0256 AC: 54 AN: 2110

Alfa AF: 0.0166 Hom.: 110

Bravo AF: 0.0385

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000830

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Alstrom syndrome (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.50
PhyloP100		0.18
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)		0.010		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: rs10199680; hg19: chr2-73761942;