rs61730765

Variant names:

• chr2-151526245-T-C
• rs61730765
• NM_001164507.2:c.21963A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001164508.2(NEB):​c.21963A>G​(p.Lys7321Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 1,611,434 control chromosomes in the GnomAD database, including 501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.029 (89 hom., cov: 32)
  • Exomes 𝑓: 0.021 (412 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.394
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-151526245-T-C is Benign according to our data. Variant chr2-151526245-T-C is described in ClinVar as Benign. ClinVar VariationId is 129729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.394 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0525 is higher than 0.05.

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.21963A>G	p.Lys7321Lys	synonymous	Exon 149 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.21963A>G	p.Lys7321Lys	synonymous	Exon 149 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.22068A>G	p.Lys7356Lys	synonymous	Exon 150 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.21963A>G	p.Lys7321Lys	synonymous	Exon 149 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.21963A>G	p.Lys7321Lys	synonymous	Exon 149 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.16860A>G	p.Lys5620Lys	synonymous	Exon 122 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.0290 AC: 4406 AN: 152116 Hom.: 88 Cov.: 32

Gnomad AFR AF: 0.0542

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0202 AC: 4926 AN: 244162 AF XY: 0.0191

Gnomad AFR exome AF: 0.0540

Gnomad AMR exome AF: 0.00928

Gnomad ASJ exome AF: 0.0222

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0366

Gnomad NFE exome AF: 0.0223

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0214 AC: 31194 AN: 1459200 Hom.: 412 Cov.: 32 AF XY: 0.0206 AC XY: 14967 AN XY: 725660

African (AFR) AF: 0.0590 AC: 1973 AN: 33446

American (AMR) AF: 0.0103 AC: 456 AN: 44398

Ashkenazi Jewish (ASJ) AF: 0.0230 AC: 599 AN: 26068

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39604

South Asian (SAS) AF: 0.00702 AC: 604 AN: 85988

European-Finnish (FIN) AF: 0.0352 AC: 1878 AN: 53280

Middle Eastern (MID) AF: 0.0103 AC: 59 AN: 5740

European-Non Finnish (NFE) AF: 0.0219 AC: 24362 AN: 1110384

Other (OTH) AF: 0.0209 AC: 1262 AN: 60292

GnomAD4 genome AF: 0.0290 AC: 4419 AN: 152234 Hom.: 89 Cov.: 32 AF XY: 0.0295 AC XY: 2193 AN XY: 74442

African (AFR) AF: 0.0544 AC: 2258 AN: 41528

American (AMR) AF: 0.0130 AC: 198 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 98 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4822

European-Finnish (FIN) AF: 0.0406 AC: 431 AN: 10614

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0197 AC: 1340 AN: 68008

Other (OTH) AF: 0.0284 AC: 60 AN: 2112

Alfa AF: 0.0244 Hom.: 42

Bravo AF: 0.0291

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Nemaline myopathy 2 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.2
DANN	Benign	0.50
PhyloP100		0.39
Mutation Taster		=99/1	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: rs61730765; hg19: chr2-152382759;