2-73419240-C-G

Variant names:

• chr2-73419240-C-G
• rs375838474
• NM_001378454.1:c.568C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015120.4(ALMS1):​c.568C>G​(p.Leu190Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L190M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALMS1 NM_015120.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.835
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07230663).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	NM_001378454.1	MANE Select	c.568C>G	p.Leu190Val	missense	Exon 3 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.568C>G	p.Leu190Val	missense	Exon 3 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.568C>G	p.Leu190Val	missense	Exon 3 of 23	ENSP00000482968.1
	ALMS1	ENST00000484298.5	TSL:1	c.442C>G	p.Leu148Val	missense	Exon 2 of 22	ENSP00000478155.1
	ALMS1	ENST00000684548.1		c.118C>G	p.Leu40Val	missense	Exon 1 of 21	ENSP00000507421.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	5.0
DANN	Benign	0.71
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.38	N
PhyloP100		-0.83
PrimateAI	Benign	0.24	T
Sift4G	Benign	0.27	T
Polyphen		0.035	B
Vest4		0.24
MutPred		0.24		Gain of glycosylation at T185 (P = 0.2352)
MVP		0.15
ClinPred		0.048	T
GERP RS		-8.3
PromoterAI		0.0032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.020
gMVP		0.046
Mutation Taster		=96/4	polymorphism

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: rs375838474; hg19: chr2-73646368;