2-151633722-C-T

Variant names:

• chr2-151633722-C-T
• rs193042896
• NM_001164507.2:c.9346G>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_001164508.2(NEB):​c.9346G>A​(p.Glu3116Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,613,984 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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. E3116D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (13 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0300
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011828959).
• BP6: Variant 2-151633722-C-T is Benign according to our data. Variant chr2-151633722-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 384148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00171 (2495/1461688) while in subpopulation MID AF = 0.0052 (30/5768). AF 95% confidence interval is 0.00374. There are 13 homozygotes in GnomAdExome4. There are 1326 alleles in the male GnomAdExome4 subpopulation. Median coverage is 115. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 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.9346G>A	p.Glu3116Lys	missense	Exon 65 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.9346G>A	p.Glu3116Lys	missense	Exon 65 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.9346G>A	p.Glu3116Lys	missense	Exon 65 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.9346G>A	p.Glu3116Lys	missense	Exon 65 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.9346G>A	p.Glu3116Lys	missense	Exon 65 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.8854-2544G>A		intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 210 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00212 AC: 527 AN: 249118 AF XY: 0.00218

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000898

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.000696

Gnomad NFE exome AF: 0.00198

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00171 AC: 2495 AN: 1461688 Hom.: 13 Cov.: 115 AF XY: 0.00182 AC XY: 1326 AN XY: 727124

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.000760 AC: 34 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 447 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00262 AC: 226 AN: 86252

European-Finnish (FIN) AF: 0.00109 AC: 58 AN: 53402

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.00139 AC: 1549 AN: 1111856

Other (OTH) AF: 0.00230 AC: 139 AN: 60372

GnomAD4 genome AF: 0.00137 AC: 209 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74468

African (AFR) AF: 0.000313 AC: 13 AN: 41558

American (AMR) AF: 0.000720 AC: 11 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4832

European-Finnish (FIN) AF: 0.000943 AC: 10 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00159 AC: 108 AN: 68042

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00190 Hom.: 0

Bravo AF: 0.00134

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00251 AC: 8

ExAC AF: 0.00220 AC: 266

EpiCase AF: 0.00316

EpiControl AF: 0.00285

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	Nemaline myopathy 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.5
DANN	Benign	0.97
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.030
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.13
Sift	Benign	0.57	T
Sift4G	Uncertain	0.028	D
Vest4		0.29
MVP		0.43
MPC		0.057
ClinPred		0.023	T
GERP RS		0.66
gMVP		0.047
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: rs193042896; hg19: chr2-152490236; COSMIC: COSV99429406;