NM_001164507.2:c.21519C>T

Variant names:

• chr2-151531795-G-A
• rs16830170
• NM_001164507.2:c.21519C>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_001164507.2(NEB):​c.21519C>T​(p.Ser7173Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,606,344 control chromosomes in the GnomAD database, including 110 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 0.0099 (30 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (80 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0580
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 2-151531795-G-A is Benign according to our data. Variant chr2-151531795-G-A is described in ClinVar as Benign. ClinVar VariationId is 129725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.058 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00988 (1504/152280) while in subpopulation SAS AF = 0.0299 (144/4816). AF 95% confidence interval is 0.0281. There are 30 homozygotes in GnomAd4. There are 731 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 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.21519C>T	p.Ser7173Ser	synonymous	Exon 144 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.21519C>T	p.Ser7173Ser	synonymous	Exon 144 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.21624C>T	p.Ser7208Ser	synonymous	Exon 145 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.21519C>T	p.Ser7173Ser	synonymous	Exon 144 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.21519C>T	p.Ser7173Ser	synonymous	Exon 144 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.16416C>T	p.Ser5472Ser	synonymous	Exon 117 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00985 AC: 1499 AN: 152162 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00770

Gnomad SAS AF: 0.0299

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00607 AC: 1493 AN: 245872 AF XY: 0.00652

Gnomad AFR exome AF: 0.0297

Gnomad AMR exome AF: 0.00187

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00568

Gnomad FIN exome AF: 0.000234

Gnomad NFE exome AF: 0.000458

Gnomad OTH exome AF: 0.00501

GnomAD4 exome AF: 0.00320 AC: 4653 AN: 1454064 Hom.: 80 Cov.: 31 AF XY: 0.00380 AC XY: 2750 AN XY: 723358

African (AFR) AF: 0.0291 AC: 969 AN: 33290

American (AMR) AF: 0.00178 AC: 79 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.0142 AC: 562 AN: 39612

South Asian (SAS) AF: 0.0267 AC: 2279 AN: 85424

European-Finnish (FIN) AF: 0.000413 AC: 22 AN: 53284

Middle Eastern (MID) AF: 0.00261 AC: 15 AN: 5756

European-Non Finnish (NFE) AF: 0.000411 AC: 455 AN: 1105982

Other (OTH) AF: 0.00452 AC: 272 AN: 60164

GnomAD4 genome AF: 0.00988 AC: 1504 AN: 152280 Hom.: 30 Cov.: 33 AF XY: 0.00982 AC XY: 731 AN XY: 74454

African (AFR) AF: 0.0295 AC: 1224 AN: 41558

American (AMR) AF: 0.00327 AC: 50 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00772 AC: 40 AN: 5184

South Asian (SAS) AF: 0.0299 AC: 144 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000514 AC: 35 AN: 68030

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00850 Hom.: 17

Bravo AF: 0.0103

Asia WGS AF: 0.0260 AC: 91 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	4.9
DANN	Benign	0.66
PhyloP100		-0.058
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs16830170; hg19: chr2-152388309; COSMIC: COSV106356915; COSMIC: COSV106356915;