chr2-151485559-T-A

Position:

• chr2-151485559-T-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001164507.2(NEB):​c.*201A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 430,904 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0029 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (7 hom.)
• Consequence: NEB NM_001164507.2 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.414

Genes affected

NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-151485559-T-A is Benign according to our data. Variant chr2-151485559-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 893482.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00293 (446/152338) while in subpopulation NFE AF= 0.00385 (262/68034). AF 95% confidence interval is 0.00347. There are 4 homozygotes in gnomad4. There are 248 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.*201A>T		3_prime_UTR_variant	182/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.*201A>T		3_prime_UTR_variant	182/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.*201A>T		3_prime_UTR_variant	182/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.*201A>T		3_prime_UTR_variant	182/182	5	NM_001164507.2	ENSP00000416578	A2

Frequencies

GnomAD3 genomes AF: 0.00293 AC: 446 AN: 152220 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00385

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00326 AC: 909 AN: 278566 Hom.: 7 Cov.: 4 AF XY: 0.00328 AC XY: 467 AN XY: 142420

Gnomad4 AFR exome AF: 0.000232

Gnomad4 AMR exome AF: 0.000513

Gnomad4 ASJ exome AF: 0.00476

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0110

Gnomad4 NFE exome AF: 0.00326

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.00293 AC: 446 AN: 152338 Hom.: 4 Cov.: 32 AF XY: 0.00333 AC XY: 248 AN XY: 74498

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0134

Gnomad4 NFE AF: 0.00385

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00752 Hom.: 3

Bravo AF: 0.00134

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

NEB: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.6
DANN	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs190132249; hg19: chr2-152342073;