rs2516294

Variant names:

• chr5-179820747-G-A
• rs2516294
• NM_001142298.2:c.-47-2211G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-179820747-G-A
• chr5-179820747-G-C
• chr5-179820747-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001142298.2(SQSTM1):​c.-47-2211G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 503,212 control chromosomes in the GnomAD database, including 576 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.044 (476 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (100 hom.)
• Consequence: SQSTM1 NM_001142298.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0170
• Publications: 1 publications found

Genes affected

SQSTM1 (HGNC:11280): (sequestosome 1) This gene encodes a multifunctional protein that binds ubiquitin and regulates activation of the nuclear factor kappa-B (NF-kB) signaling pathway. The protein functions as a scaffolding/adaptor protein in concert with TNF receptor-associated factor 6 to mediate activation of NF-kB in response to upstream signals. Alternatively spliced transcript variants encoding either the same or different isoforms have been identified for this gene. Mutations in this gene result in sporadic and familial Paget disease of bone. [provided by RefSeq, Mar 2009]

SQSTM1 Gene-Disease associations (from GenCC):

• neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• frontotemporal dementia and/or amyotrophic lateral sclerosis 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• osteosarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Paget disease of bone 3

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• behavioral variant of frontotemporal dementia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• frontotemporal dementia with motor neuron disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000301422 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 5-179820747-G-A is Benign according to our data. Variant chr5-179820747-G-A is described in ClinVar as [Benign]. Clinvar id is 1261854.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_001142298.2	c.-47-2211G>A		intron_variant	Intron 2 of 8		NP_001135770.1
SQSTM1	NM_001142299.2	c.-47-2211G>A		intron_variant	Intron 2 of 8		NP_001135771.1
SQSTM1	NM_003900.5	c.-190G>A		upstream_gene_variant		ENST00000389805.9	NP_003891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.-190G>A		upstream_gene_variant		1	NM_003900.5	ENSP00000374455.4

Frequencies

GnomAD3 genomes AF: 0.0437 AC: 6651 AN: 152134 Hom.: 477 Cov.: 33

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.0358

GnomAD4 exome AF: 0.00489 AC: 1715 AN: 350960 Hom.: 100 Cov.: 5 AF XY: 0.00396 AC XY: 726 AN XY: 183320

African (AFR) AF: 0.149 AC: 1132 AN: 7620

American (AMR) AF: 0.0162 AC: 126 AN: 7788

Ashkenazi Jewish (ASJ) AF: 0.00232 AC: 25 AN: 10774

East Asian (EAS) AF: 0.00 AC: 0 AN: 22960

South Asian (SAS) AF: 0.000410 AC: 11 AN: 26840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27344

Middle Eastern (MID) AF: 0.0112 AC: 18 AN: 1612

European-Non Finnish (NFE) AF: 0.000453 AC: 102 AN: 225076

Other (OTH) AF: 0.0144 AC: 301 AN: 20946

GnomAD4 genome AF: 0.0438 AC: 6662 AN: 152252 Hom.: 476 Cov.: 33 AF XY: 0.0412 AC XY: 3070 AN XY: 74450

African (AFR) AF: 0.149 AC: 6174 AN: 41526

American (AMR) AF: 0.0225 AC: 344 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 68002

Other (OTH) AF: 0.0354 AC: 75 AN: 2116

Alfa AF: 0.00215 Hom.: 4

Bravo AF: 0.0519

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.2
DANN	Benign	0.85
PhyloP100		-0.017
PromoterAI		-0.0084	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2516294; hg19: chr5-179247747;