rs193224180

Variant names:

• chr2-151503408-G-A
• rs193224180
• NM_001164507.2:c.23776C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BS1 BS2_Supporting

The NM_001164508.2(NEB):​c.23776C>T​(p.Pro7926Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00181 in 1,612,560 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:4
• Conservation: PhyloP100: 3.94
• Publications: 5 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

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021578938).
• BP6: Variant 2-151503408-G-A is Benign according to our data. Variant chr2-151503408-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194312.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00135 (205/152262) while in subpopulation NFE AF = 0.00256 (174/68010). AF 95% confidence interval is 0.00225. There are 0 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.23776C>T	p.Pro7926Ser	missense	Exon 166 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.23776C>T	p.Pro7926Ser	missense	Exon 166 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.23881C>T	p.Pro7961Ser	missense	Exon 167 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.23776C>T	p.Pro7926Ser	missense	Exon 166 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.23776C>T	p.Pro7926Ser	missense	Exon 166 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.18673C>T	p.Pro6225Ser	missense	Exon 139 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00256

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00110 AC: 274 AN: 248950 AF XY: 0.00107

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00198

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.00186 AC: 2719 AN: 1460298 Hom.: 6 Cov.: 29 AF XY: 0.00173 AC XY: 1260 AN XY: 726472

African (AFR) AF: 0.000389 AC: 13 AN: 33428

American (AMR) AF: 0.00112 AC: 50 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00228 AC: 2532 AN: 1110780

Other (OTH) AF: 0.00194 AC: 117 AN: 60328

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74446

African (AFR) AF: 0.000313 AC: 13 AN: 41568

American (AMR) AF: 0.000654 AC: 10 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00256 AC: 174 AN: 68010

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.00128

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000546 AC: 2

ESP6500EA AF: 0.00293 AC: 24

ExAC AF: 0.000952 AC: 115

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	not provided (5)
-	2	1	Nemaline myopathy 2 (3)
-	1	1	not specified (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	NEB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.13
Sift	Benign	0.32	T
Sift4G	Uncertain	0.016	D
Polyphen		0.20	B
Vest4		0.63
MVP		0.38
MPC		0.33
ClinPred		0.051	T
GERP RS		5.4
Varity_R		0.21
gMVP		0.31
Mutation Taster		=245/55	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs193224180; hg19: chr2-152359922;