chr2-201728463-TA-T

Variant names:

• chr2-201728463-TA-T
• rs141560438
• NM_020919.4:c.2841+48delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020919.4(ALS2):​c.2841+48delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0457 in 1,609,216 control chromosomes in the GnomAD database, including 1,885 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (112 hom., cov: 31)
  • Exomes 𝑓: 0.047 (1773 hom.)
• Consequence: ALS2 NM_020919.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.954
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 2-201728463-TA-T is Benign according to our data. Variant chr2-201728463-TA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0506 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	NM_020919.4	MANE Select	c.2841+48delT		intron	N/A	NP_065970.2
	ALS2	NM_001410975.1		c.2841+48delT		intron	N/A	NP_001397904.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	ENST00000264276.11	TSL:1 MANE Select	c.2841+48delT		intron	N/A	ENSP00000264276.6
	ALS2	ENST00000482891.6	TSL:1	n.3183+48delT		intron	N/A
	ALS2	ENST00000679416.1		n.3231delT		non_coding_transcript_exon	Exon 15 of 32

Frequencies

GnomAD3 genomes AF: 0.0344 AC: 5235 AN: 152148 Hom.: 112 Cov.: 31

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0315

Gnomad ASJ AF: 0.0335

Gnomad EAS AF: 0.0125

Gnomad SAS AF: 0.0404

Gnomad FIN AF: 0.0314

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0501

Gnomad OTH AF: 0.0387

GnomAD2 exomes AF: 0.0392 AC: 9758 AN: 249202 AF XY: 0.0415

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.0260

Gnomad ASJ exome AF: 0.0359

Gnomad EAS exome AF: 0.0115

Gnomad FIN exome AF: 0.0328

Gnomad NFE exome AF: 0.0505

Gnomad OTH exome AF: 0.0460

GnomAD4 exome AF: 0.0469 AC: 68278 AN: 1456950 Hom.: 1773 Cov.: 29 AF XY: 0.0473 AC XY: 34336 AN XY: 725236

African (AFR) AF: 0.0112 AC: 375 AN: 33380

American (AMR) AF: 0.0276 AC: 1233 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 949 AN: 26110

East Asian (EAS) AF: 0.00800 AC: 317 AN: 39646

South Asian (SAS) AF: 0.0491 AC: 4232 AN: 86130

European-Finnish (FIN) AF: 0.0342 AC: 1823 AN: 53334

Middle Eastern (MID) AF: 0.0403 AC: 232 AN: 5754

European-Non Finnish (NFE) AF: 0.0509 AC: 56386 AN: 1107666

Other (OTH) AF: 0.0454 AC: 2731 AN: 60214

GnomAD4 genome AF: 0.0344 AC: 5236 AN: 152266 Hom.: 112 Cov.: 31 AF XY: 0.0330 AC XY: 2456 AN XY: 74430

African (AFR) AF: 0.0128 AC: 533 AN: 41562

American (AMR) AF: 0.0315 AC: 482 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0335 AC: 116 AN: 3466

East Asian (EAS) AF: 0.0125 AC: 65 AN: 5180

South Asian (SAS) AF: 0.0409 AC: 197 AN: 4818

European-Finnish (FIN) AF: 0.0314 AC: 333 AN: 10614

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0501 AC: 3408 AN: 68000

Other (OTH) AF: 0.0383 AC: 81 AN: 2116

Alfa AF: 0.0260 Hom.: 26

Bravo AF: 0.0328

Asia WGS AF: 0.0230 AC: 81 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Aug 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.95
Mutation Taster		=100/0	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: rs141560438; hg19: chr2-202593186;