rs41270201

Variant names:

• chr2-151508075-G-A
• rs41270201
• NM_001164507.2:c.23381C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164508.2(NEB):​c.23381C>T​(p.Ser7794Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,609,282 control chromosomes in the GnomAD database, including 531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S7794S) has been classified as Likely benign. The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.016 (24 hom., cov: 33)
  • Exomes 𝑓: 0.024 (507 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 9.35
• Publications: 8 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]

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Specifications for NEB are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008599877).
• BP6: Variant 2-151508075-G-A is Benign according to our data. Variant chr2-151508075-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0164 (2497/152236) while in subpopulation NFE AF = 0.027 (1838/68028). AF 95% confidence interval is 0.026. There are 24 homozygotes in GnomAd4. There are 1126 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AD,AR gene

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.23381C>T	p.Ser7794Leu	missense	Exon 162 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.23381C>T	p.Ser7794Leu	missense	Exon 162 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.23486C>T	p.Ser7829Leu	missense	Exon 163 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.23381C>T	p.Ser7794Leu	missense	Exon 162 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.23381C>T	p.Ser7794Leu	missense	Exon 162 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.18278C>T	p.Ser6093Leu	missense	Exon 135 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2497 AN: 152118 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.00454

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0197

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0175 AC: 4228 AN: 242286 AF XY: 0.0174

Gnomad AFR exome AF: 0.00484

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.00194

Gnomad EAS exome AF: 0.0000563

Gnomad FIN exome AF: 0.0248

Gnomad NFE exome AF: 0.0280

Gnomad OTH exome AF: 0.0176

GnomAD4 exome AF: 0.0237 AC: 34500 AN: 1457046 Hom.: 507 Cov.: 30 AF XY: 0.0230 AC XY: 16637 AN XY: 724446

African (AFR) AF: 0.00338 AC: 113 AN: 33436

American (AMR) AF: 0.0124 AC: 551 AN: 44348

Ashkenazi Jewish (ASJ) AF: 0.00255 AC: 66 AN: 25918

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39654

South Asian (SAS) AF: 0.00137 AC: 117 AN: 85252

European-Finnish (FIN) AF: 0.0270 AC: 1435 AN: 53196

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5764

European-Non Finnish (NFE) AF: 0.0281 AC: 31142 AN: 1109276

Other (OTH) AF: 0.0176 AC: 1060 AN: 60202

GnomAD4 genome AF: 0.0164 AC: 2497 AN: 152236 Hom.: 24 Cov.: 33 AF XY: 0.0151 AC XY: 1126 AN XY: 74418

African (AFR) AF: 0.00453 AC: 188 AN: 41536

American (AMR) AF: 0.0137 AC: 209 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4818

European-Finnish (FIN) AF: 0.0197 AC: 209 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0270 AC: 1838 AN: 68028

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.0244 Hom.: 196

Bravo AF: 0.0158

TwinsUK AF: 0.0283 AC: 105

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.00597 AC: 22

ESP6500EA AF: 0.0272 AC: 223

ExAC AF: 0.0176 AC: 2121

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Nemaline myopathy 2 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.27
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.46
MPC		0.25
ClinPred		0.0096	T
GERP RS		5.3
PromoterAI		-0.026	Neutral
Varity_R		0.28
gMVP		0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41270201; hg19: chr2-152364589;