NEB p.Pro65Leu

Variant names:

• chr2-151727791-G-A
• rs375909006
• NM_001164507.2:c.194C>T
• NEB p.Pro65Leu

Your query was ambiguous. Multiple possible variants found:

• chr2-151727791-G-A
• chr2-151727790-CG-AA
• chr2-151727790-CG-GA
• chr2-151727790-CG-TA
• chr2-151727791-GG-AA
• chr2-151727790-CGG-TAA

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-3 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -3 classification points (ACMG Germline Pathogenicity v2019). BP4_ModerateBP6

The NM_001164508.2(NEB):c.194C>T (p.Pro65Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000147 (AC=237) in the gnomAD database across 1,613,694 control chromosomes, including 3 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00862. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P65= (synonymous): Likely_benign (ClinVar VariationId 1129905, 1 star); p.P65= (synonymous): Benign/Likely_benign (ClinVar VariationId 95125, 2 stars)

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (3 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3 O:1
• Conservation: PhyloP100: 2.39
• Publications: 3 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Natera, Myriad Women's Health, Ambry Genetics, 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

Classification according to ACMG Germline Pathogenicity v2019

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

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001164508.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NEB NM_001164507.2	MANE Plus Clinical	c.194C>T p.Pro65Leu	missense	Exon 5 of 182	Prot: NP_001157979.2 UniProt:
	NEB NM_001164508.2	MANE Select	c.194C>T p.Pro65Leu	missense	Exon 5 of 182	Prot: NP_001157980.2 UniProt:
	NEB NM_001271208.2		c.194C>T p.Pro65Leu	missense	Exon 5 of 183	Prot: NP_001258137.2

NEB NM_001164507.2

MANE Plus Clinical

HGVSc / HGVSpc.194C>Tp.Pro65Leu

Exon rankExon 5 of 182

missense

Prot: NP_001157979.2UniProt: P20929-3

NEB NM_001164508.2

MANE Select

HGVSc / HGVSpc.194C>Tp.Pro65Leu

Exon rankExon 5 of 182

missense

Prot: NP_001157980.2UniProt: P20929-2

NEB NM_001271208.2

HGVSc / HGVSpc.194C>Tp.Pro65Leu

Exon rankExon 5 of 183

missense

Prot: NP_001258137.2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NEB ENST00000397345.8	TSL:5MANE Select	c.194C>T p.Pro65Leu	missense	Exon 5 of 182	Prot: ENSP00000380505.3 UniProt:
	NEB ENST00000427231.7	TSL:5MANE Plus Clinical	c.194C>T p.Pro65Leu	missense	Exon 5 of 182	Prot: ENSP00000416578.2 UniProt:
	NEB ENST00000409198.5	TSL:5	c.194C>T p.Pro65Leu	missense	Exon 5 of 150	Prot: ENSP00000386259.1 UniProt:

NEB ENST00000397345.8

TSL:5MANE Select

HGVSc / HGVSpc.194C>Tp.Pro65Leu

Exon rankExon 5 of 182

missense

Prot: ENSP00000380505.3UniProt: P20929-2

NEB ENST00000427231.7

TSL:5MANE Plus Clinical

HGVSc / HGVSpc.194C>Tp.Pro65Leu

Exon rankExon 5 of 182

missense

Prot: ENSP00000416578.2UniProt: P20929-3

NEB ENST00000409198.5

TSL:5

HGVSc / HGVSpc.194C>Tp.Pro65Leu

Exon rankExon 5 of 150

missense

Prot: ENSP00000386259.1UniProt: P20929-4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000986	AC:15	Hom:0	AN:152170	Cov:33
GnomAD2 exomes	AF: 0.000125	AC:31	Hom:	AN:248882	Cov:
GnomAD4 exome	AF: 0.000152	AC:222	Hom:3	AN:1461406	Cov:31
GnomAD4 genome	AF: 0.0000985	AC:15	Hom:0	AN:152288	Cov:33
TOPMed (Bravo)	AF: 0.000140	AC:37	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000141	AC:9	Hom:0	AN:63936	Cov:
Local & regional cohorts 7 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000854	AC:2	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.000164	AC:2	Hom:	AN:12162	Cov:
Qatari Genome	AF: 0.0341	AC:6	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000410	AC:5	Hom:0	AN:122316	Cov:
Turkish Variome	AF: 0.000744	AC:5	Hom:0	AN:6720	Cov:
UK10K	AF: 0.000132	AC:1	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000112	AC:1	Hom:0	AN:8960	Cov:

Showing 13 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00 *	0	11108	0.000114 *	2	17618
BipEx(Bipolar disorder (including schizoaffective))	0.000106	3	28420	0.000104	3	28842
Epi25(Epilepsy)	0.000238	10	41958	0.000105	7	66872
SCHEMA(Schizophrenia)	0.000139	17	121926	0.000126	24	190718

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
FuncVEP CTI	Benign	0.31
GPN-Star LLR	N/A	-5.1
GPN-Star score	N/A	5.1
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.98	T
Mutation Taster	N/A	2/98	disease causing
MutationAssessor	Benign	0.69	N
PhyloP100	Benign	2.4
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.021	D
Varity_R	N/A	0.25
VESM-3B	Benign	-5.8

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs375909006;

hg19: chr2-152584305;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar