rs3821324

Variant names:

• chr2-151485796-G-A
• rs3821324
• NM_001164507.2:c.25542C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-151485796-G-A
• chr2-151485796-G-C
• chr2-151485796-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001164508.2(NEB):​c.25542C>T​(p.Thr8514Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,612,818 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T8514T) has been classified as Likely benign. The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0024 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (32 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.22
• Publications: 2 publications found

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

Specifications for NEB are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.073).
• BP6: Variant 2-151485796-G-A is Benign according to our data. Variant chr2-151485796-G-A is described in ClinVar as Benign. ClinVar VariationId is 194578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00237 (361/152264) while in subpopulation EAS AF = 0.0457 (237/5182). AF 95% confidence interval is 0.041. There are 9 homozygotes in GnomAd4. There are 186 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164508.2. 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
	NEB	NM_001164507.2	MANE Plus Clinical	c.25542C>T	p.Thr8514Thr	synonymous	Exon 182 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.25542C>T	p.Thr8514Thr	synonymous	Exon 182 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.25647C>T	p.Thr8549Thr	synonymous	Exon 183 of 183	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.25542C>T	p.Thr8514Thr	synonymous	Exon 182 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.25542C>T	p.Thr8514Thr	synonymous	Exon 182 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.19974C>T	p.Thr6658Thr	synonymous	Exon 150 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 364 AN: 152146 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0464

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00543 AC: 1348 AN: 248224 AF XY: 0.00503

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0484

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000383

Gnomad OTH exome AF: 0.00299

GnomAD4 exome AF: 0.00161 AC: 2357 AN: 1460554 Hom.: 32 Cov.: 31 AF XY: 0.00154 AC XY: 1122 AN XY: 726380

African (AFR) AF: 0.000418 AC: 14 AN: 33466

American (AMR) AF: 0.00969 AC: 433 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.0311 AC: 1233 AN: 39670

South Asian (SAS) AF: 0.00190 AC: 164 AN: 86118

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53366

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5758

European-Non Finnish (NFE) AF: 0.000240 AC: 267 AN: 1111056

Other (OTH) AF: 0.00401 AC: 242 AN: 60338

GnomAD4 genome AF: 0.00237 AC: 361 AN: 152264 Hom.: 9 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74454

African (AFR) AF: 0.000529 AC: 22 AN: 41552

American (AMR) AF: 0.00379 AC: 58 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0457 AC: 237 AN: 5182

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68016

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00120 Hom.: 1

Bravo AF: 0.00321

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.000657

EpiControl AF: 0.000476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Nemaline myopathy 2 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	1.9
DANN	Benign	0.82
PhyloP100		-1.2
Mutation Taster		=97/3	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: rs3821324; hg19: chr2-152342310; COSMIC: COSV51426418; COSMIC: COSV51426418;