rs144957142

Variant names:

• chr14-23392607-C-T
• rs144957142
• NM_002471.4:c.3297G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_002471.4(MYH6):​c.3297G>A​(p.Glu1099Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,607,288 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00086 (1 hom., cov: 26)
  • Exomes 𝑓: 0.000097 (1 hom.)
• Consequence: MYH6 NM_002471.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.675
• Publications: 1 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=-0.4).
• BP6: Variant 14-23392607-C-T is Benign according to our data. Variant chr14-23392607-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.675 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000859 (129/150190) while in subpopulation AFR AF = 0.00301 (123/40798). AF 95% confidence interval is 0.00258. There are 1 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 129 AD gene.

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.3297G>A	p.Glu1099Glu	synonymous	Exon 25 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.3297G>A	p.Glu1099Glu	synonymous	Exon 25 of 39	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.3330G>A	p.Glu1110Glu	synonymous	Exon 25 of 39	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.3297G>A	p.Glu1099Glu	synonymous	Exon 25 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.000846 AC: 127 AN: 150072 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.000486

GnomAD2 exomes AF: 0.000262 AC: 66 AN: 251488 AF XY: 0.000221

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000968 AC: 141 AN: 1457098 Hom.: 1 Cov.: 35 AF XY: 0.000102 AC XY: 74 AN XY: 724784

African (AFR) AF: 0.00276 AC: 92 AN: 33368

American (AMR) AF: 0.000337 AC: 15 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39254

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1108898

Other (OTH) AF: 0.000150 AC: 9 AN: 60060

GnomAD4 genome AF: 0.000859 AC: 129 AN: 150190 Hom.: 1 Cov.: 26 AF XY: 0.000860 AC XY: 63 AN XY: 73238

African (AFR) AF: 0.00301 AC: 123 AN: 40798

American (AMR) AF: 0.000133 AC: 2 AN: 15032

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5044

South Asian (SAS) AF: 0.00 AC: 0 AN: 4682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67700

Other (OTH) AF: 0.000481 AC: 1 AN: 2080

Alfa AF: 0.000747 Hom.: 0

Bravo AF: 0.000782

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	1.4
DANN	Benign	0.49
PhyloP100		-0.68
Mutation Taster		=99/1	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: rs144957142; hg19: chr14-23861816;