chr2-151576297-A-T

Variant names:

• chr2-151576297-A-T
• rs35227368
• NM_001164507.2:c.16762T>A

Variant summary

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

The NM_001164508.2(NEB):​c.16762T>A​(p.Ser5588Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0153 in 1,609,038 control chromosomes in the GnomAD database, including 1,208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S5588S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.038 (308 hom., cov: 30)
  • Exomes 𝑓: 0.013 (900 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.01
• Publications: 10 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=0.0019331276).
• BP6: Variant 2-151576297-A-T is Benign according to our data. Variant chr2-151576297-A-T is described in ClinVar as Benign. ClinVar VariationId is 129710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

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.16762T>A	p.Ser5588Thr	missense	Exon 106 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.16762T>A	p.Ser5588Thr	missense	Exon 106 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.16762T>A	p.Ser5588Thr	missense	Exon 106 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.16762T>A	p.Ser5588Thr	missense	Exon 106 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.16762T>A	p.Ser5588Thr	missense	Exon 106 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.11659T>A	p.Ser3887Thr	missense	Exon 79 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.0378 AC: 5700 AN: 150874 Hom.: 298 Cov.: 30

Gnomad AFR AF: 0.0982

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.0318

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.0740

Gnomad FIN AF: 0.0000971

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00196

Gnomad OTH AF: 0.0383

GnomAD2 exomes AF: 0.0282 AC: 7005 AN: 248574 AF XY: 0.0286

Gnomad AFR exome AF: 0.0979

Gnomad AMR exome AF: 0.00587

Gnomad ASJ exome AF: 0.0325

Gnomad EAS exome AF: 0.149

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00211

Gnomad OTH exome AF: 0.0174

GnomAD4 exome AF: 0.0129 AC: 18880 AN: 1458050 Hom.: 900 Cov.: 31 AF XY: 0.0143 AC XY: 10365 AN XY: 725402

African (AFR) AF: 0.102 AC: 3427 AN: 33444

American (AMR) AF: 0.00620 AC: 277 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 843 AN: 26066

East Asian (EAS) AF: 0.139 AC: 5515 AN: 39662

South Asian (SAS) AF: 0.0653 AC: 5605 AN: 85840

European-Finnish (FIN) AF: 0.000357 AC: 19 AN: 53248

Middle Eastern (MID) AF: 0.0148 AC: 85 AN: 5736

European-Non Finnish (NFE) AF: 0.00147 AC: 1629 AN: 1109200

Other (OTH) AF: 0.0246 AC: 1480 AN: 60156

GnomAD4 genome AF: 0.0380 AC: 5736 AN: 150988 Hom.: 308 Cov.: 30 AF XY: 0.0383 AC XY: 2824 AN XY: 73740

African (AFR) AF: 0.0982 AC: 4033 AN: 41062

American (AMR) AF: 0.0154 AC: 233 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.0318 AC: 110 AN: 3464

East Asian (EAS) AF: 0.149 AC: 763 AN: 5128

South Asian (SAS) AF: 0.0744 AC: 356 AN: 4782

European-Finnish (FIN) AF: 0.0000971 AC: 1 AN: 10298

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00196 AC: 133 AN: 67822

Other (OTH) AF: 0.0480 AC: 100 AN: 2082

Alfa AF: 0.0140 Hom.: 19

Bravo AF: 0.0402

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.0941 AC: 358

ESP6500EA AF: 0.00291 AC: 24

ExAC AF: 0.0307 AC: 3706

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Nemaline myopathy 2 (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		5.0
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.20
Sift	Uncertain	0.011	D
Sift4G	Benign	0.089	T
Polyphen		0.98	D
Vest4		0.41
MPC		0.33
ClinPred		0.037	T
GERP RS		5.9
Varity_R		0.30
gMVP		0.65
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: rs35227368; hg19: chr2-152432811; COSMIC: COSV107247334;