2-151674563-A-G

Variant names:

• chr2-151674563-A-G
• rs6711382
• NM_001164507.2:c.3901T>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.3901T>C​(p.Tyr1301His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.861 in 1,612,734 control chromosomes in the GnomAD database, including 604,938 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1301C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.81 (50716 hom., cov: 32)
  • Exomes 𝑓: 0.87 (554222 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.86
• Publications: 37 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=6.914382E-7).
• BP6: Variant 2-151674563-A-G is Benign according to our data. Variant chr2-151674563-A-G is described in ClinVar as Benign. ClinVar VariationId is 167336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.89 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.3901T>C	p.Tyr1301His	missense	Exon 36 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.3901T>C	p.Tyr1301His	missense	Exon 36 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.3901T>C	p.Tyr1301His	missense	Exon 36 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.3901T>C	p.Tyr1301His	missense	Exon 36 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.3901T>C	p.Tyr1301His	missense	Exon 36 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.3901T>C	p.Tyr1301His	missense	Exon 36 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.808 AC: 122753 AN: 152010 Hom.: 50699 Cov.: 32

Gnomad AFR AF: 0.646

Gnomad AMI AF: 0.852

Gnomad AMR AF: 0.885

Gnomad ASJ AF: 0.846

Gnomad EAS AF: 0.575

Gnomad SAS AF: 0.721

Gnomad FIN AF: 0.889

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.896

Gnomad OTH AF: 0.831

GnomAD2 exomes AF: 0.834 AC: 207597 AN: 249066 AF XY: 0.832

Gnomad AFR exome AF: 0.640

Gnomad AMR exome AF: 0.913

Gnomad ASJ exome AF: 0.839

Gnomad EAS exome AF: 0.595

Gnomad FIN exome AF: 0.882

Gnomad NFE exome AF: 0.895

Gnomad OTH exome AF: 0.853

GnomAD4 exome AF: 0.867 AC: 1266546 AN: 1460606 Hom.: 554222 Cov.: 39 AF XY: 0.864 AC XY: 627693 AN XY: 726652

African (AFR) AF: 0.637 AC: 21316 AN: 33442

American (AMR) AF: 0.909 AC: 40615 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.843 AC: 22033 AN: 26126

East Asian (EAS) AF: 0.550 AC: 21807 AN: 39668

South Asian (SAS) AF: 0.724 AC: 62396 AN: 86164

European-Finnish (FIN) AF: 0.883 AC: 47129 AN: 53394

Middle Eastern (MID) AF: 0.864 AC: 4983 AN: 5768

European-Non Finnish (NFE) AF: 0.896 AC: 995430 AN: 1111012

Other (OTH) AF: 0.843 AC: 50837 AN: 60328

GnomAD4 genome AF: 0.807 AC: 122809 AN: 152128 Hom.: 50716 Cov.: 32 AF XY: 0.807 AC XY: 60004 AN XY: 74382

African (AFR) AF: 0.646 AC: 26762 AN: 41446

American (AMR) AF: 0.885 AC: 13547 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.846 AC: 2936 AN: 3472

East Asian (EAS) AF: 0.575 AC: 2965 AN: 5160

South Asian (SAS) AF: 0.721 AC: 3478 AN: 4826

European-Finnish (FIN) AF: 0.889 AC: 9426 AN: 10602

Middle Eastern (MID) AF: 0.888 AC: 261 AN: 294

European-Non Finnish (NFE) AF: 0.896 AC: 60925 AN: 68008

Other (OTH) AF: 0.822 AC: 1732 AN: 2106

Alfa AF: 0.863 Hom.: 238328

Bravo AF: 0.801

TwinsUK AF: 0.904 AC: 3352

ALSPAC AF: 0.897 AC: 3456

ESP6500AA AF: 0.660 AC: 2596

ESP6500EA AF: 0.892 AC: 7412

ExAC AF: 0.826 AC: 99831

Asia WGS AF: 0.615 AC: 2142 AN: 3478

EpiCase AF: 0.902

EpiControl AF: 0.896

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Nemaline myopathy 2 (3)
-	-	2	not specified (2)
-	-	1	Arthrogryposis multiplex congenita 6 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.040
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.0090	T
MetaRNN	Benign	6.9e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.4	N
PhyloP100		1.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.11
Sift	Benign	0.46	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.13
MPC		0.063
ClinPred		0.0057	T
GERP RS		5.5
Varity_R		0.032
gMVP		0.16
Mutation Taster		=99/1	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: rs6711382; hg19: chr2-152531077; COSMIC: COSV51459151; COSMIC: COSV51459151;