NM_001164507.2:c.5971C>T

Variant names:

• chr2-151659169-G-A
• rs75807392
• NM_001164507.2:c.5971C>T

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.5971C>T​(p.His1991Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0658 in 1,598,366 control chromosomes in the GnomAD database, including 5,482 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1991Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.054 (421 hom., cov: 32)
  • Exomes 𝑓: 0.067 (5061 hom.)
• Consequence: NEB NM_001164507.2 missense, splice_region
• Scores: Splicing: ADA: 0.0002484
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 3.47
• Publications: 13 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=0.0014465153).
• BP6: Variant 2-151659169-G-A is Benign according to our data. Variant chr2-151659169-G-A is described in ClinVar as Benign. ClinVar VariationId is 129752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.259 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.5971C>T	p.His1991Tyr	missense splice_region	Exon 47 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.5971C>T	p.His1991Tyr	missense splice_region	Exon 47 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.5971C>T	p.His1991Tyr	missense splice_region	Exon 47 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.5971C>T	p.His1991Tyr	missense splice_region	Exon 47 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.5971C>T	p.His1991Tyr	missense splice_region	Exon 47 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.5971C>T	p.His1991Tyr	missense splice_region	Exon 47 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.0545 AC: 8278 AN: 151952 Hom.: 423 Cov.: 32

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0441

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0939

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0546

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.0772 AC: 19116 AN: 247700 AF XY: 0.0788

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.0465

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.257

Gnomad FIN exome AF: 0.0990

Gnomad NFE exome AF: 0.0567

Gnomad OTH exome AF: 0.0675

GnomAD4 exome AF: 0.0670 AC: 96971 AN: 1446296 Hom.: 5061 Cov.: 29 AF XY: 0.0684 AC XY: 49242 AN XY: 720148

African (AFR) AF: 0.0163 AC: 538 AN: 32936

American (AMR) AF: 0.0476 AC: 2116 AN: 44440

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 478 AN: 25952

East Asian (EAS) AF: 0.310 AC: 12249 AN: 39552

South Asian (SAS) AF: 0.115 AC: 9870 AN: 85576

European-Finnish (FIN) AF: 0.0978 AC: 5218 AN: 53354

Middle Eastern (MID) AF: 0.0386 AC: 221 AN: 5732

European-Non Finnish (NFE) AF: 0.0566 AC: 62157 AN: 1098928

Other (OTH) AF: 0.0689 AC: 4124 AN: 59826

GnomAD4 genome AF: 0.0544 AC: 8274 AN: 152070 Hom.: 421 Cov.: 32 AF XY: 0.0581 AC XY: 4318 AN XY: 74308

African (AFR) AF: 0.0178 AC: 740 AN: 41504

American (AMR) AF: 0.0442 AC: 675 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 61 AN: 3470

East Asian (EAS) AF: 0.271 AC: 1398 AN: 5160

South Asian (SAS) AF: 0.118 AC: 569 AN: 4814

European-Finnish (FIN) AF: 0.0939 AC: 991 AN: 10558

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0545 AC: 3706 AN: 67978

Other (OTH) AF: 0.0416 AC: 88 AN: 2114

Alfa AF: 0.0594 Hom.: 1405

Bravo AF: 0.0488

TwinsUK AF: 0.0539 AC: 200

ALSPAC AF: 0.0535 AC: 206

ESP6500AA AF: 0.0158 AC: 58

ESP6500EA AF: 0.0540 AC: 442

ExAC AF: 0.0772 AC: 9322

EpiCase AF: 0.0467

EpiControl AF: 0.0486

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Nemaline myopathy 2 (4)
-	-	1	Arthrogryposis multiplex congenita 6 (1)
-	-	1	Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Benign	0.44
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.049
Sift	Benign	1.0	T
Sift4G	Benign	0.077	T
Polyphen		0.68	P
Vest4		0.33
MPC		0.058
ClinPred		0.030	T
GERP RS		4.4
Varity_R		0.043
gMVP		0.38
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.046
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: rs75807392; hg19: chr2-152515683; COSMIC: COSV51458616;