rs144180493

Variant names:

• chr2-151663756-A-C
• rs144180493
• NM_001164507.2:c.5555T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-151663756-A-C
• chr2-151663756-A-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.5555T>G​(p.Met1852Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00507 in 1,613,850 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1852V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (30 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 9.32
• 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=0.01530838).
• BP6: Variant 2-151663756-A-C is Benign according to our data. Variant chr2-151663756-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197524.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00331 (504/152302) while in subpopulation NFE AF = 0.0057 (388/68028). AF 95% confidence interval is 0.00524. There are 2 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.5555T>G	p.Met1852Arg	missense	Exon 45 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.5555T>G	p.Met1852Arg	missense	Exon 45 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.5555T>G	p.Met1852Arg	missense	Exon 45 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.5555T>G	p.Met1852Arg	missense	Exon 45 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.5555T>G	p.Met1852Arg	missense	Exon 45 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.5555T>G	p.Met1852Arg	missense	Exon 45 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00331 AC: 503 AN: 152184 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00570

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00332 AC: 826 AN: 249030 AF XY: 0.00309

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00221

Gnomad ASJ exome AF: 0.00388

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000928

Gnomad NFE exome AF: 0.00538

Gnomad OTH exome AF: 0.00331

GnomAD4 exome AF: 0.00526 AC: 7683 AN: 1461548 Hom.: 30 Cov.: 31 AF XY: 0.00515 AC XY: 3745 AN XY: 727058

African (AFR) AF: 0.000956 AC: 32 AN: 33464

American (AMR) AF: 0.00244 AC: 109 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00387 AC: 101 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00124 AC: 107 AN: 86256

European-Finnish (FIN) AF: 0.00122 AC: 65 AN: 53390

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.00631 AC: 7019 AN: 1111782

Other (OTH) AF: 0.00404 AC: 244 AN: 60364

GnomAD4 genome AF: 0.00331 AC: 504 AN: 152302 Hom.: 2 Cov.: 32 AF XY: 0.00273 AC XY: 203 AN XY: 74466

African (AFR) AF: 0.00115 AC: 48 AN: 41574

American (AMR) AF: 0.00229 AC: 35 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00570 AC: 388 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00521 Hom.: 6

Bravo AF: 0.00344

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.000504 AC: 2

ESP6500EA AF: 0.00492 AC: 41

ExAC AF: 0.00329 AC: 398

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00556

EpiControl AF: 0.00474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	1	2	Nemaline myopathy 2 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.72	P
Vest4		0.86
MVP		0.65
MPC		0.35
ClinPred		0.026	T
GERP RS		5.5
Varity_R		0.89
gMVP		0.60
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: rs144180493; hg19: chr2-152520270;