NM_001164507.2:c.21720C>T

Variant names:

• chr2-151529225-G-A
• rs34718443
• NM_001164507.2:c.21720C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001164507.2(NEB):​c.21720C>T​(p.Tyr7240Tyr) variant causes a synonymous change. The variant allele was found at a frequency of 0.0019 in 1,611,584 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (28 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 4.37
• Publications: 3 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-151529225-G-A is Benign according to our data. Variant chr2-151529225-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129726.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00177 (269/152354) while in subpopulation SAS AF = 0.00456 (22/4826). AF 95% confidence interval is 0.00309. There are 2 homozygotes in GnomAd4. There are 113 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. 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.21720C>T	p.Tyr7240Tyr	synonymous	Exon 146 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.21720C>T	p.Tyr7240Tyr	synonymous	Exon 146 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.21825C>T	p.Tyr7275Tyr	synonymous	Exon 147 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.21720C>T	p.Tyr7240Tyr	synonymous	Exon 146 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.21720C>T	p.Tyr7240Tyr	synonymous	Exon 146 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.16617C>T	p.Tyr5539Tyr	synonymous	Exon 119 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 270 AN: 152236 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00268 AC: 668 AN: 249044 AF XY: 0.00281

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.0300

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00192 AC: 2801 AN: 1459230 Hom.: 28 Cov.: 30 AF XY: 0.00205 AC XY: 1490 AN XY: 726052

African (AFR) AF: 0.000329 AC: 11 AN: 33416

American (AMR) AF: 0.00141 AC: 63 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0303 AC: 791 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00498 AC: 429 AN: 86176

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53398

Middle Eastern (MID) AF: 0.00556 AC: 32 AN: 5760

European-Non Finnish (NFE) AF: 0.00113 AC: 1251 AN: 1109678

Other (OTH) AF: 0.00368 AC: 222 AN: 60286

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152354 Hom.: 2 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74512

African (AFR) AF: 0.000168 AC: 7 AN: 41576

American (AMR) AF: 0.00105 AC: 16 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00157 AC: 107 AN: 68036

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00290 Hom.: 2

Bravo AF: 0.00186

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00243

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Nemaline myopathy 2 (4)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	4.2
DANN	Benign	0.66
PhyloP100		4.4
Mutation Taster		=96/4	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: rs34718443; hg19: chr2-152385739;