rs114089598

Variant names:

• chr2-151667874-T-C
• rs114089598
• NM_001164507.2:c.4649A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-151667874-T-C
• chr2-151667874-T-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001164508.2(NEB):​c.4649A>G​(p.Lys1550Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 1,612,620 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K1550K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (12 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8
• Conservation: PhyloP100: 3.49
• Publications: 6 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008101642).
• BP6: Variant 2-151667874-T-C is Benign according to our data. Variant chr2-151667874-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95132.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00303 (462/152342) while in subpopulation NFE AF = 0.00447 (304/68030). AF 95% confidence interval is 0.00406. There are 4 homozygotes in GnomAd4. There are 223 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.4649A>G	p.Lys1550Arg	missense	Exon 40 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.4649A>G	p.Lys1550Arg	missense	Exon 40 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.4649A>G	p.Lys1550Arg	missense	Exon 40 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.4649A>G	p.Lys1550Arg	missense	Exon 40 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.4649A>G	p.Lys1550Arg	missense	Exon 40 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.4649A>G	p.Lys1550Arg	missense	Exon 40 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 462 AN: 152224 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00447

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00269 AC: 670 AN: 248810 AF XY: 0.00273

Gnomad AFR exome AF: 0.000582

Gnomad AMR exome AF: 0.00224

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00506

Gnomad NFE exome AF: 0.00395

Gnomad OTH exome AF: 0.00431

GnomAD4 exome AF: 0.00392 AC: 5727 AN: 1460278 Hom.: 12 Cov.: 30 AF XY: 0.00374 AC XY: 2717 AN XY: 726478

African (AFR) AF: 0.000478 AC: 16 AN: 33448

American (AMR) AF: 0.00257 AC: 115 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.000728 AC: 19 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86124

European-Finnish (FIN) AF: 0.00656 AC: 350 AN: 53354

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00450 AC: 4997 AN: 1110836

Other (OTH) AF: 0.00378 AC: 228 AN: 60294

GnomAD4 genome AF: 0.00303 AC: 462 AN: 152342 Hom.: 4 Cov.: 32 AF XY: 0.00299 AC XY: 223 AN XY: 74492

African (AFR) AF: 0.000794 AC: 33 AN: 41576

American (AMR) AF: 0.00373 AC: 57 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00452 AC: 48 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00447 AC: 304 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00330 Hom.: 8

Bravo AF: 0.00315

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000821 AC: 3

ESP6500EA AF: 0.00368 AC: 30

ExAC AF: 0.00242 AC: 292

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	5	not provided (7)
-	1	2	Nemaline myopathy 2 (3)
-	-	1	NEB-related disorder (1)
-	1	-	Nemaline Myopathy, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.27
Sift	Benign	0.073	T
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.26
MVP		0.56
MPC		0.32
ClinPred		0.039	T
GERP RS		5.9
Varity_R		0.21
gMVP		0.20
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs114089598; hg19: chr2-152524388; COSMIC: COSV51446735;