rs117271684

Variant names:

• chr2-151665469-A-G
• rs117271684
• NM_001164507.2:c.5102T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164508.2(NEB):​c.5102T>C​(p.Val1701Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00313 in 1,611,368 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (110 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 6.13
• Publications: 10 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]

NEB Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen
• autosomal dominant nebulin-related myopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027567446).
• BP6: Variant 2-151665469-A-G is Benign according to our data. Variant chr2-151665469-A-G is described in ClinVar as Benign. ClinVar VariationId is 129745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0635 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.5102T>C	p.Val1701Ala	missense	Exon 42 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.5102T>C	p.Val1701Ala	missense	Exon 42 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.5102T>C	p.Val1701Ala	missense	Exon 42 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.5102T>C	p.Val1701Ala	missense	Exon 42 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.5102T>C	p.Val1701Ala	missense	Exon 42 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.5102T>C	p.Val1701Ala	missense	Exon 42 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00427 AC: 644 AN: 150994 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.000536

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00804

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0698

Gnomad SAS AF: 0.00319

Gnomad FIN AF: 0.00810

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000517

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00880 AC: 2168 AN: 246388 AF XY: 0.00817

Gnomad AFR exome AF: 0.000328

Gnomad AMR exome AF: 0.0135

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0770

Gnomad FIN exome AF: 0.00688

Gnomad NFE exome AF: 0.000698

Gnomad OTH exome AF: 0.00568

GnomAD4 exome AF: 0.00301 AC: 4393 AN: 1460256 Hom.: 110 Cov.: 31 AF XY: 0.00296 AC XY: 2151 AN XY: 726258

African (AFR) AF: 0.000179 AC: 6 AN: 33466

American (AMR) AF: 0.0127 AC: 565 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.0654 AC: 2592 AN: 39656

South Asian (SAS) AF: 0.00210 AC: 180 AN: 85848

European-Finnish (FIN) AF: 0.00794 AC: 423 AN: 53282

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.000263 AC: 292 AN: 1111332

Other (OTH) AF: 0.00552 AC: 333 AN: 60322

GnomAD4 genome AF: 0.00426 AC: 643 AN: 151112 Hom.: 15 Cov.: 32 AF XY: 0.00476 AC XY: 351 AN XY: 73814

African (AFR) AF: 0.000535 AC: 22 AN: 41144

American (AMR) AF: 0.00803 AC: 122 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.0694 AC: 357 AN: 5142

South Asian (SAS) AF: 0.00319 AC: 15 AN: 4700

European-Finnish (FIN) AF: 0.00810 AC: 85 AN: 10490

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

European-Non Finnish (NFE) AF: 0.000517 AC: 35 AN: 67698

Other (OTH) AF: 0.00332 AC: 7 AN: 2106

Alfa AF: 0.00326 Hom.: 57

Bravo AF: 0.00467

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000258 AC: 1

ESP6500EA AF: 0.000484 AC: 4

ExAC AF: 0.00804 AC: 971

Asia WGS AF: 0.0250 AC: 86 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L
PhyloP100		6.1
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.11
Sift	Benign	0.29	T
Sift4G	Pathogenic	0.0010	D
Polyphen		0.62	P
Vest4		0.51
MVP		0.32
MPC		0.27
ClinPred		0.038	T
GERP RS		4.8
Varity_R		0.19
gMVP		0.47
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: rs117271684; hg19: chr2-152521983; COSMIC: COSV50874194; COSMIC: COSV50874194;