chr2-151496329-C-G

Variant names:

• chr2-151496329-C-G
• rs7575451
• NM_001164507.2:c.24433G>C

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.24433G>C​(p.Ala8145Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 1,610,432 control chromosomes in the GnomAD database, including 339,213 homozygotes. In-silico tool predicts 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. A8145T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.64 (31482 hom., cov: 31)
  • Exomes 𝑓: 0.65 (307731 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.99
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.199028E-6).
• BP6: Variant 2-151496329-C-G is Benign according to our data. Variant chr2-151496329-C-G is described in ClinVar as Benign. ClinVar VariationId is 95120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.752 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.24433G>C	p.Ala8145Pro	missense	Exon 173 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.24433G>C	p.Ala8145Pro	missense	Exon 173 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.24538G>C	p.Ala8180Pro	missense	Exon 174 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.24433G>C	p.Ala8145Pro	missense	Exon 173 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.24433G>C	p.Ala8145Pro	missense	Exon 173 of 182	ENSP00000416578.2	P20929-3
	RIF1	ENST00000457745.1	TSL:1	n.578+1003C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.640 AC: 97174 AN: 151872 Hom.: 31435 Cov.: 31

Gnomad AFR AF: 0.591

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.722

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.773

Gnomad SAS AF: 0.518

Gnomad FIN AF: 0.685

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.648

Gnomad OTH AF: 0.645

GnomAD2 exomes AF: 0.649 AC: 158963 AN: 245028 AF XY: 0.638

Gnomad AFR exome AF: 0.592

Gnomad AMR exome AF: 0.753

Gnomad ASJ exome AF: 0.576

Gnomad EAS exome AF: 0.772

Gnomad FIN exome AF: 0.675

Gnomad NFE exome AF: 0.644

Gnomad OTH exome AF: 0.658

GnomAD4 exome AF: 0.647 AC: 943926 AN: 1458442 Hom.: 307731 Cov.: 55 AF XY: 0.642 AC XY: 465678 AN XY: 725246

African (AFR) AF: 0.599 AC: 20054 AN: 33456

American (AMR) AF: 0.746 AC: 33138 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 14943 AN: 26056

East Asian (EAS) AF: 0.795 AC: 31471 AN: 39604

South Asian (SAS) AF: 0.512 AC: 43935 AN: 85738

European-Finnish (FIN) AF: 0.677 AC: 36027 AN: 53236

Middle Eastern (MID) AF: 0.636 AC: 3669 AN: 5766

European-Non Finnish (NFE) AF: 0.650 AC: 721719 AN: 1109932

Other (OTH) AF: 0.647 AC: 38970 AN: 60216

GnomAD4 genome AF: 0.640 AC: 97286 AN: 151990 Hom.: 31482 Cov.: 31 AF XY: 0.644 AC XY: 47794 AN XY: 74256

African (AFR) AF: 0.591 AC: 24508 AN: 41442

American (AMR) AF: 0.722 AC: 11030 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 1976 AN: 3468

East Asian (EAS) AF: 0.772 AC: 4000 AN: 5180

South Asian (SAS) AF: 0.519 AC: 2500 AN: 4814

European-Finnish (FIN) AF: 0.685 AC: 7222 AN: 10538

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.648 AC: 44018 AN: 67964

Other (OTH) AF: 0.650 AC: 1368 AN: 2106

Alfa AF: 0.645 Hom.: 10237

Bravo AF: 0.645

TwinsUK AF: 0.654 AC: 2425

ALSPAC AF: 0.634 AC: 2443

ESP6500AA AF: 0.595 AC: 2203

ESP6500EA AF: 0.644 AC: 5281

ExAC AF: 0.639 AC: 77175

Asia WGS AF: 0.637 AC: 2216 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Nemaline myopathy 2 (4)
-	-	3	not provided (3)
-	-	1	Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0078	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.010	T
MetaRNN	Benign	0.0000052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N
PhyloP100		2.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	2.4	N
REVEL	Uncertain	0.46
Sift	Benign	0.94	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.15
MPC		0.31
ClinPred		0.017	T
GERP RS		4.1
Varity_R		0.051
gMVP		0.22
Mutation Taster		=98/2	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: rs7575451; hg19: chr2-152352843; COSMIC: COSV51426793; COSMIC: COSV51426793;