2-201757758-G-C

Variant names:

• chr2-201757758-G-C
• rs190369242
• NM_020919.4:c.1115C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020919.4(ALS2):​c.1115C>G​(p.Pro372Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,603,366 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00097 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: ALS2 NM_020919.4 missense, splice_region
• Scores: Splicing: ADA: 0.0004038
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 1.88
• Publications: 10 publications found

Genes affected

ALS2 (HGNC:443): (alsin Rho guanine nucleotide exchange factor ALS2) The protein encoded by this gene contains an ATS1/RCC1-like domain, a RhoGEF domain, and a vacuolar protein sorting 9 (VPS9) domain, all of which are guanine-nucleotide exchange factors that activate members of the Ras superfamily of GTPases. The protein functions as a guanine nucleotide exchange factor for the small GTPase RAB5. The protein localizes with RAB5 on early endosomal compartments, and functions as a modulator for endosomal dynamics. Mutations in this gene result in several forms of juvenile lateral sclerosis and infantile-onset ascending spastic paralysis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

ALS2 Gene-Disease associations (from GenCC):

• ALS2-related motor neuron disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• amyotrophic lateral sclerosis type 2, juvenile

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• infantile-onset ascending hereditary spastic paralysis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• juvenile primary lateral sclerosis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0146540105).
• BP6: Variant 2-201757758-G-C is Benign according to our data. Variant chr2-201757758-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241307.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000972 (148/152248) while in subpopulation AMR AF = 0.00164 (25/15290). AF 95% confidence interval is 0.00126. There are 1 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020919.4. 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
	ALS2	NM_020919.4	MANE Select	c.1115C>G	p.Pro372Arg	missense splice_region	Exon 5 of 34	NP_065970.2
	ALS2	NM_001410975.1		c.1115C>G	p.Pro372Arg	missense splice_region	Exon 5 of 34	NP_001397904.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	ENST00000264276.11	TSL:1 MANE Select	c.1115C>G	p.Pro372Arg	missense splice_region	Exon 5 of 34	ENSP00000264276.6
	ALS2	ENST00000482789.6	TSL:1	n.1457C>G		splice_region non_coding_transcript_exon	Exon 5 of 13
	ALS2	ENST00000482891.6	TSL:1	n.1457C>G		splice_region non_coding_transcript_exon	Exon 5 of 22

Frequencies

GnomAD3 genomes AF: 0.000973 AC: 148 AN: 152130 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00108 AC: 260 AN: 240124 AF XY: 0.00121

Gnomad AFR exome AF: 0.000196

Gnomad AMR exome AF: 0.000700

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000602

Gnomad NFE exome AF: 0.00150

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.00146 AC: 2124 AN: 1451118 Hom.: 3 Cov.: 31 AF XY: 0.00149 AC XY: 1079 AN XY: 722482

African (AFR) AF: 0.000420 AC: 14 AN: 33370

American (AMR) AF: 0.000672 AC: 30 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00245 AC: 211 AN: 86130

European-Finnish (FIN) AF: 0.000106 AC: 5 AN: 47284

Middle Eastern (MID) AF: 0.00590 AC: 34 AN: 5764

European-Non Finnish (NFE) AF: 0.00155 AC: 1712 AN: 1107916

Other (OTH) AF: 0.00184 AC: 111 AN: 60242

GnomAD4 genome AF: 0.000972 AC: 148 AN: 152248 Hom.: 1 Cov.: 32 AF XY: 0.000954 AC XY: 71 AN XY: 74434

African (AFR) AF: 0.000241 AC: 10 AN: 41558

American (AMR) AF: 0.00164 AC: 25 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00150 AC: 102 AN: 68010

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00132 Hom.: 1

Bravo AF: 0.000982

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000270 AC: 1

ESP6500EA AF: 0.00208 AC: 17

ExAC AF: 0.00107 AC: 129

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00148

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	ALS2-related disorder (1)
-	-	1	Amyotrophic lateral sclerosis type 2, juvenile (1)
-	1	-	Hereditary spastic paraplegia (1)
-	-	1	Infantile-onset ascending hereditary spastic paralysis (1)
-	1	-	Juvenile primary lateral sclerosis;C1859807:Amyotrophic lateral sclerosis type 2, juvenile;C2931441:Infantile-onset ascending hereditary spastic paralysis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.12
Sift	Benign	0.53	T
Sift4G	Benign	0.49	T
Polyphen		0.53	P
Vest4		0.55
MVP		0.67
MPC		0.48
ClinPred		0.021	T
GERP RS		4.6
Varity_R		0.049
gMVP		0.32
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00040
dbscSNV1_RF	Benign	0.014
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: rs190369242; hg19: chr2-202622481; COSMIC: COSV105081148; COSMIC: COSV105081148;