Genetic Variant NM_032578.4:c.1104C>T (chr10-68145500-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_032578.4(MYPN):c.1104C>T(p.Gly368Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,613,020 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 7 hom. )

Consequence

MYPN
NM_032578.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 1.14

Publications

4 publications found

Variant links:

Genes affected

MYPN (HGNC:23246): (myopalladin) Striated muscle in vertebrates comprises large proteins which must be organized properly to contract efficiently. Z-lines in striated muscle are a sign of this organization, representing the ends of actin thin filaments, titin, nebulin or nebulette and accessory proteins required for structure and function. This gene encodes a protein which interacts with nebulin in skeletal muscle or nebulette in cardiac muscle and alpha-actinin. In addition, this gene product can interact with a protein with the I-band indicating it has a regulatory as well as structural function. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]

MYPN Gene-Disease associations (from GenCC):

MYPN-related myopathy
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
cap myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
childhood-onset nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial isolated restrictive cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
dilated cardiomyopathy 1KK
Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MYPN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

BP6

Variant 10-68145500-C-T is Benign according to our data. Variant chr10-68145500-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 31836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.14 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00158 (241/152152) while in subpopulation NFE AF = 0.00298 (203/68008). AF 95% confidence interval is 0.00265. There are 1 homozygotes in GnomAd4. There are 99 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032578.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYPN	NM_032578.4	MANE Select	c.1104C>T	p.Gly368Gly	synonymous	Exon 4 of 20	NP_115967.2
MYPN	NM_001256267.2		c.1104C>T	p.Gly368Gly	synonymous	Exon 5 of 21	NP_001243196.1
MYPN	NM_001256268.2		c.222C>T	p.Gly74Gly	synonymous	Exon 8 of 24	NP_001243197.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYPN	ENST00000358913.10	TSL:1 MANE Select	c.1104C>T	p.Gly368Gly	synonymous	Exon 4 of 20	ENSP00000351790.5
MYPN	ENST00000540630.6	TSL:1	c.1158C>T	p.Gly386Gly	synonymous	Exon 4 of 20	ENSP00000441668.3
MYPN	ENST00000613327.5	TSL:1	c.1104C>T	p.Gly368Gly	synonymous	Exon 5 of 21	ENSP00000480757.2

Frequencies

GnomAD3 genomes

AF:

0.00159

AC:

241

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000852

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000947

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00298

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00149

AC:

374

AN:

251082

AF XY:

0.00146

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.00267

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00223

AC:

3264

AN:

1460868

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

1590

AN XY:

726762

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33448

American (AMR)

AF:

0.000872

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.000919

AC:

AN:

26112

East Asian (EAS)

AF:

0.000177

AC:

AN:

39648

South Asian (SAS)

AF:

0.000197

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000169

AC:

AN:

53252

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00274

AC:

3043

AN:

1111332

Other (OTH)

AF:

0.00181

AC:

109

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.424

Heterozygous variant carriers

146

292

437

583

729

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00158

AC:

241

AN:

152152

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41504

American (AMR)

AF:

0.000850

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000947

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00298

AC:

203

AN:

68008

Other (OTH)

AF:

0.00142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00234

Hom.:

Bravo

AF:

0.00186

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00365

EpiControl

AF:

0.00379

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Dilated cardiomyopathy 1KK (3)

not provided (3)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.66

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over