rs189623595

Variant names:

• chr2-151687639-T-C
• rs189623595
• NM_001164507.2:c.2510A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BS1 BS2_Supporting

The NM_001164508.2(NEB):​c.2510A>G​(p.Lys837Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000593 in 1,612,828 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (2 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8
• Conservation: PhyloP100: -0.0430
• Publications: 4 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052112937).
• BP6: Variant 2-151687639-T-C is Benign according to our data. Variant chr2-151687639-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287622.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00117 (178/152312) while in subpopulation AFR AF = 0.00265 (110/41570). AF 95% confidence interval is 0.00224. There are 0 homozygotes in GnomAd4. There are 91 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.2510A>G	p.Lys837Arg	missense	Exon 26 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.2510A>G	p.Lys837Arg	missense	Exon 26 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.2510A>G	p.Lys837Arg	missense	Exon 26 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.2510A>G	p.Lys837Arg	missense	Exon 26 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.2510A>G	p.Lys837Arg	missense	Exon 26 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.2510A>G	p.Lys837Arg	missense	Exon 26 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 178 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000930 AC: 228 AN: 245282 AF XY: 0.000902

Gnomad AFR exome AF: 0.00269

Gnomad AMR exome AF: 0.00141

Gnomad ASJ exome AF: 0.00740

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000470

Gnomad OTH exome AF: 0.00184

GnomAD4 exome AF: 0.000533 AC: 778 AN: 1460516 Hom.: 2 Cov.: 32 AF XY: 0.000523 AC XY: 380 AN XY: 726452

African (AFR) AF: 0.00293 AC: 98 AN: 33466

American (AMR) AF: 0.00128 AC: 57 AN: 44470

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 188 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86180

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53336

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5766

European-Non Finnish (NFE) AF: 0.000311 AC: 346 AN: 1111170

Other (OTH) AF: 0.00106 AC: 64 AN: 60336

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74468

African (AFR) AF: 0.00265 AC: 110 AN: 41570

American (AMR) AF: 0.00144 AC: 22 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000913 Hom.: 0

Bravo AF: 0.00140

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00231 AC: 9

ESP6500EA AF: 0.000965 AC: 8

ExAC AF: 0.000894 AC: 108

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	1	2	Nemaline myopathy 2 (3)
-	-	1	NEB-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.2
DANN	Benign	0.96
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N
PhyloP100		-0.043
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.097
Sift	Benign	0.25	T
Sift4G	Benign	0.45	T
Polyphen		0.0010	B
Vest4		0.17
MVP		0.33
MPC		0.046
ClinPred		0.0058	T
GERP RS		-4.9
Varity_R		0.049
gMVP		0.093
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: rs189623595; hg19: chr2-152544153; COSMIC: COSV99428110; COSMIC: COSV99428110;