NM_001164507.2:c.13721A>G

Variant names:

• chr2-151600509-T-C
• rs876657542
• NM_001164507.2:c.13721A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_001164507.2(NEB):​c.13721A>G​(p.His4574Arg) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. H4574H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.071 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.11
• Publications: 0 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=0.2096799).
• BP6: Variant 2-151600509-T-C is Benign according to our data. Variant chr2-151600509-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.13721A>G	p.His4574Arg	missense	Exon 89 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.13721A>G	p.His4574Arg	missense	Exon 89 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.13721A>G	p.His4574Arg	missense	Exon 89 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.13721A>G	p.His4574Arg	missense	Exon 89 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.13721A>G	p.His4574Arg	missense	Exon 89 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.11601+9300A>G		intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AC: 0 AN: 0 Hom.: 0 Cov.: 0

GnomAD2 exomes AF: 0.474 AC: 1658 AN: 3496 AF XY: 0.474

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.472

Gnomad ASJ exome AF: 0.500

Gnomad EAS exome AF: 0.462

Gnomad FIN exome AF: 0.423

Gnomad NFE exome AF: 0.445

Gnomad OTH exome AF: 0.475

GnomAD4 exome AF: 0.0709 AC: 96 AN: 1354 Hom.: 0 Cov.: 0 AF XY: 0.0595 AC XY: 42 AN XY: 706

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.0867 AC: 34 AN: 392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.115 AC: 3 AN: 26

South Asian (SAS) AF: 0.0714 AC: 11 AN: 154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0622 AC: 45 AN: 724

Other (OTH) AF: 0.0714 AC: 3 AN: 42

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

Alfa AF: 0.409 Hom.: 39

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Benign	0.45
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
PhyloP100		6.1
PROVEAN	Benign	0.080	N
REVEL	Benign	0.057
Sift	Benign	0.099	T
Sift4G	Uncertain	0.037	D
Vest4		0.15
MutPred		0.45		Gain of helix (P = 0.132)
MPC		0.15
ClinPred		0.016	T
GERP RS		2.5
gMVP		0.0016
Mutation Taster		=97/3	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: rs876657542; hg19: chr2-152457023;