rs200719359

Variant names:

• chr2-151724333-T-C
• rs200719359
• NM_001164507.2:c.539A>G

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.539A>G​(p.Lys180Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000629 in 1,612,666 control chromosomes in the GnomAD database, including 21 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. K180K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00040 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00065 (20 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 7.60
• Publications: 5 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=0.008422345).
• BP6: Variant 2-151724333-T-C is Benign according to our data. Variant chr2-151724333-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198810.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000401 (61/152164) while in subpopulation SAS AF = 0.00813 (39/4796). AF 95% confidence interval is 0.00611. There are 1 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 20 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.539A>G	p.Lys180Arg	missense	Exon 8 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.539A>G	p.Lys180Arg	missense	Exon 8 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.539A>G	p.Lys180Arg	missense	Exon 8 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.539A>G	p.Lys180Arg	missense	Exon 8 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.539A>G	p.Lys180Arg	missense	Exon 8 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.539A>G	p.Lys180Arg	missense	Exon 8 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152046 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00813

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00123 AC: 304 AN: 247322 AF XY: 0.00169

Gnomad AFR exome AF: 0.0000652

Gnomad AMR exome AF: 0.000380

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000241

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000653 AC: 954 AN: 1460502 Hom.: 20 Cov.: 30 AF XY: 0.000940 AC XY: 683 AN XY: 726352

African (AFR) AF: 0.0000598 AC: 2 AN: 33458

American (AMR) AF: 0.000359 AC: 16 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26098

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39676

South Asian (SAS) AF: 0.00861 AC: 739 AN: 85876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5764

European-Non Finnish (NFE) AF: 0.000126 AC: 140 AN: 1111392

Other (OTH) AF: 0.000547 AC: 33 AN: 60328

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152164 Hom.: 1 Cov.: 31 AF XY: 0.000632 AC XY: 47 AN XY: 74378

African (AFR) AF: 0.0000241 AC: 1 AN: 41524

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00813 AC: 39 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000324 Hom.: 1

Bravo AF: 0.000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.00135 AC: 163

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	Nemaline myopathy 2 (4)
-	2	2	not provided (4)
-	-	1	Arthrogryposis multiplex congenita 6 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.032	T
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.0	L
PhyloP100		7.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.34
Sift	Benign	0.082	T
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.55
MVP		0.66
MPC		0.31
ClinPred		0.048	T
GERP RS		6.0
Varity_R		0.18
gMVP		0.41
Mutation Taster		=99/1	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: rs200719359; hg19: chr2-152580847;