rs184262608

Variant names:

• chr2-151659071-C-T
• rs184262608
• NM_001164507.2:c.6069G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001271208.2(NEB):​c.6069G>A​(p.Met2023Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00826 in 1,596,242 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2023V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0065 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (66 hom.)
• Consequence: NEB NM_001271208.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.968
• 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: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• 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=0.011434644).
• BP6: Variant 2-151659071-C-T is Benign according to our data. Variant chr2-151659071-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00648 (987/152244) while in subpopulation NFE AF = 0.0105 (714/68030). AF 95% confidence interval is 0.00986. There are 8 homozygotes in GnomAd4. There are 485 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271208.2. 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.6069G>A	p.Met2023Ile	missense	Exon 47 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.6069G>A	p.Met2023Ile	missense	Exon 47 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.6069G>A	p.Met2023Ile	missense	Exon 47 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.6069G>A	p.Met2023Ile	missense	Exon 47 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.6069G>A	p.Met2023Ile	missense	Exon 47 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.6069G>A	p.Met2023Ile	missense	Exon 47 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00649 AC: 987 AN: 152126 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00764

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00642 AC: 1598 AN: 248750 AF XY: 0.00640

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00293

Gnomad ASJ exome AF: 0.00368

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00808

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00779

GnomAD4 exome AF: 0.00845 AC: 12198 AN: 1443998 Hom.: 66 Cov.: 29 AF XY: 0.00828 AC XY: 5958 AN XY: 719402

African (AFR) AF: 0.00139 AC: 46 AN: 33032

American (AMR) AF: 0.00275 AC: 123 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00354 AC: 92 AN: 26022

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39616

South Asian (SAS) AF: 0.00137 AC: 118 AN: 85864

European-Finnish (FIN) AF: 0.00770 AC: 411 AN: 53378

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5748

European-Non Finnish (NFE) AF: 0.0100 AC: 10959 AN: 1095828

Other (OTH) AF: 0.00737 AC: 441 AN: 59842

GnomAD4 genome AF: 0.00648 AC: 987 AN: 152244 Hom.: 8 Cov.: 32 AF XY: 0.00652 AC XY: 485 AN XY: 74428

African (AFR) AF: 0.00161 AC: 67 AN: 41548

American (AMR) AF: 0.00680 AC: 104 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4814

European-Finnish (FIN) AF: 0.00764 AC: 81 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0105 AC: 714 AN: 68030

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00927 Hom.: 16

Bravo AF: 0.00568

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00134 AC: 5

ESP6500EA AF: 0.00999 AC: 82

ExAC AF: 0.00650 AC: 785

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00939

EpiControl AF: 0.00842

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.28	N
PhyloP100		0.97
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	0.94	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.60		Gain of helix (P = 0.062)
MVP		0.25
MPC		0.056
ClinPred		0.012	T
GERP RS		5.2
Varity_R		0.29
gMVP		0.21
Mutation Taster		=100/0	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: rs184262608; hg19: chr2-152515585;