NM_002471.4:c.1335C>T

Variant names:

• chr14-23400784-G-A
• rs61731179
• NM_002471.4:c.1335C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002471.4(MYH6):​c.1335C>T​(p.Asn445Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0546 in 1,614,236 control chromosomes in the GnomAD database, including 2,878 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (189 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2689 hom.)
• Consequence: MYH6 NM_002471.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.334
• Publications: 9 publications found

Genes affected

MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]

MYH6 Gene-Disease associations (from GenCC):

• MYH-6 related congenital heart defects

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 14

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• Keppen-Lubinsky syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• atrial septal defect 3

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 14-23400784-G-A is Benign according to our data. Variant chr14-23400784-G-A is described in ClinVar as Benign. ClinVar VariationId is 44451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.334 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0674 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002471.4. 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
	MYH6	NM_002471.4	MANE Select	c.1335C>T	p.Asn445Asn	synonymous	Exon 13 of 39	NP_002462.2	P13533

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	ENST00000405093.9	TSL:5 MANE Select	c.1335C>T	p.Asn445Asn	synonymous	Exon 13 of 39	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.1335C>T	p.Asn445Asn	synonymous	Exon 13 of 39	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.1335C>T	p.Asn445Asn	synonymous	Exon 13 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 6308 AN: 152228 Hom.: 189 Cov.: 32

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0391

Gnomad ASJ AF: 0.0873

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0736

Gnomad FIN AF: 0.0392

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0590

Gnomad OTH AF: 0.0540

GnomAD2 exomes AF: 0.0532 AC: 13369 AN: 251486 AF XY: 0.0571

Gnomad AFR exome AF: 0.00917

Gnomad AMR exome AF: 0.0323

Gnomad ASJ exome AF: 0.0781

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0466

Gnomad NFE exome AF: 0.0636

Gnomad OTH exome AF: 0.0692

GnomAD4 exome AF: 0.0560 AC: 81847 AN: 1461890 Hom.: 2689 Cov.: 32 AF XY: 0.0576 AC XY: 41858 AN XY: 727246

African (AFR) AF: 0.00869 AC: 291 AN: 33480

American (AMR) AF: 0.0328 AC: 1465 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0800 AC: 2090 AN: 26136

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39700

South Asian (SAS) AF: 0.0885 AC: 7634 AN: 86258

European-Finnish (FIN) AF: 0.0495 AC: 2645 AN: 53420

Middle Eastern (MID) AF: 0.107 AC: 619 AN: 5768

European-Non Finnish (NFE) AF: 0.0574 AC: 63791 AN: 1112008

Other (OTH) AF: 0.0546 AC: 3299 AN: 60396

GnomAD4 genome AF: 0.0414 AC: 6307 AN: 152346 Hom.: 189 Cov.: 32 AF XY: 0.0414 AC XY: 3081 AN XY: 74488

African (AFR) AF: 0.0103 AC: 427 AN: 41588

American (AMR) AF: 0.0391 AC: 598 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0873 AC: 303 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.0737 AC: 355 AN: 4818

European-Finnish (FIN) AF: 0.0392 AC: 416 AN: 10624

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0590 AC: 4016 AN: 68036

Other (OTH) AF: 0.0534 AC: 113 AN: 2116

Alfa AF: 0.0533 Hom.: 130

Bravo AF: 0.0403

EpiCase AF: 0.0674

EpiControl AF: 0.0662

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy 14 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.9
DANN	Benign	0.79
PhyloP100		0.33
Mutation Taster		=100/0	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: rs61731179; hg19: chr14-23869993;