chr2-151579498-T-G

Variant names:

• chr2-151579498-T-G
• rs62174690
• NM_001164507.2:c.16544A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164507.2(NEB):​c.16544A>C​(p.Lys5515Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,353,638 control chromosomes in the GnomAD database, including 59,135 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K5515N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.19 (2913 hom., cov: 17)
  • Exomes 𝑓: 0.26 (59135 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.29
• 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: 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=0.0021787584).
• BP6: Variant 2-151579498-T-G is Benign according to our data. Variant chr2-151579498-T-G is described in ClinVar as Benign. ClinVar VariationId is 257764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.16544A>C	p.Lys5515Thr	missense	Exon 105 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.16544A>C	p.Lys5515Thr	missense	Exon 105 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.16544A>C	p.Lys5515Thr	missense	Exon 105 of 183	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.16544A>C	p.Lys5515Thr	missense	Exon 105 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.16544A>C	p.Lys5515Thr	missense	Exon 105 of 182	ENSP00000416578.2
	NEB	ENST00000413693.5	TSL:5	c.734A>C	p.Lys245Thr	missense	Exon 5 of 74	ENSP00000410961.1

Frequencies

GnomAD3 genomes AF: 0.188 AC: 23044 AN: 122878 Hom.: 2916 Cov.: 17

Gnomad AFR AF: 0.0640

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.273

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.191

GnomAD2 exomes AF: 0.286 AC: 18868 AN: 66032 AF XY: 0.285

Gnomad AFR exome AF: 0.0704

Gnomad AMR exome AF: 0.378

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.299

Gnomad FIN exome AF: 0.400

Gnomad NFE exome AF: 0.293

Gnomad OTH exome AF: 0.284

GnomAD4 exome AF: 0.261 AC: 353794 AN: 1353638 Hom.: 59135 Cov.: 30 AF XY: 0.260 AC XY: 173664 AN XY: 668744

African (AFR) AF: 0.0708 AC: 2222 AN: 31380

American (AMR) AF: 0.377 AC: 13359 AN: 35424

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 5828 AN: 25026

East Asian (EAS) AF: 0.334 AC: 11867 AN: 35548

South Asian (SAS) AF: 0.188 AC: 14789 AN: 78688

European-Finnish (FIN) AF: 0.301 AC: 14542 AN: 48358

Middle Eastern (MID) AF: 0.256 AC: 1037 AN: 4044

European-Non Finnish (NFE) AF: 0.265 AC: 275553 AN: 1038638

Other (OTH) AF: 0.258 AC: 14597 AN: 56532

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.187 AC: 23031 AN: 122966 Hom.: 2913 Cov.: 17 AF XY: 0.186 AC XY: 10817 AN XY: 58304

African (AFR) AF: 0.0639 AC: 2357 AN: 36882

American (AMR) AF: 0.292 AC: 3063 AN: 10498

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 681 AN: 3098

East Asian (EAS) AF: 0.268 AC: 1103 AN: 4114

South Asian (SAS) AF: 0.144 AC: 540 AN: 3744

European-Finnish (FIN) AF: 0.225 AC: 1546 AN: 6866

Middle Eastern (MID) AF: 0.256 AC: 65 AN: 254

European-Non Finnish (NFE) AF: 0.238 AC: 13106 AN: 55076

Other (OTH) AF: 0.189 AC: 302 AN: 1600

Alfa AF: 0.122 Hom.: 281

Bravo AF: 0.221

ExAC AF: 0.203 AC: 1260

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.85	T
PhyloP100		2.3
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.12
Sift	Benign	0.035	D
Sift4G	Uncertain	0.030	D
Vest4		0.12
MPC		0.14
ClinPred		0.0052	T
GERP RS		3.6
gMVP		0.014
Mutation Taster		=91/9	polymorphism (auto)

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: rs62174690; hg19: chr2-152436012; COSMIC: COSV50806735;