14-23390381-C-T

Variant names:

• chr14-23390381-C-T
• rs28730770
• NM_002471.4:c.3408G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_002471.4(MYH6):​c.3408G>A​(p.Lys1136Lys) variant causes a synonymous change. The variant allele was found at a frequency of 0.00287 in 1,606,144 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (70 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (49 hom.)
• Consequence: MYH6 NM_002471.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.94
• Publications: 2 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 14-23390381-C-T is Benign according to our data. Variant chr14-23390381-C-T is described in ClinVar as Benign. ClinVar VariationId is 44484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0523 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.3408G>A	p.Lys1136Lys	synonymous	Exon 26 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.3408G>A	p.Lys1136Lys	synonymous	Exon 26 of 39	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.3441G>A	p.Lys1147Lys	synonymous	Exon 26 of 39	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.3408G>A	p.Lys1136Lys	synonymous	Exon 26 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2351 AN: 151822 Hom.: 70 Cov.: 31

Gnomad AFR AF: 0.0543

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00433

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00381 AC: 913 AN: 239392 AF XY: 0.00301

Gnomad AFR exome AF: 0.0550

Gnomad AMR exome AF: 0.00314

Gnomad ASJ exome AF: 0.000406

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000157

Gnomad OTH exome AF: 0.00238

GnomAD4 exome AF: 0.00155 AC: 2251 AN: 1454204 Hom.: 49 Cov.: 34 AF XY: 0.00136 AC XY: 983 AN XY: 723194

African (AFR) AF: 0.0528 AC: 1751 AN: 33144

American (AMR) AF: 0.00351 AC: 155 AN: 44156

Ashkenazi Jewish (ASJ) AF: 0.000345 AC: 9 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39156

South Asian (SAS) AF: 0.0000819 AC: 7 AN: 85450

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50938

Middle Eastern (MID) AF: 0.00287 AC: 16 AN: 5580

European-Non Finnish (NFE) AF: 0.000103 AC: 114 AN: 1109600

Other (OTH) AF: 0.00331 AC: 199 AN: 60126

GnomAD4 genome AF: 0.0155 AC: 2352 AN: 151940 Hom.: 70 Cov.: 31 AF XY: 0.0140 AC XY: 1042 AN XY: 74292

African (AFR) AF: 0.0542 AC: 2241 AN: 41378

American (AMR) AF: 0.00433 AC: 66 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67956

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.00499 Hom.: 7

Bravo AF: 0.0172

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1EE;C2750467:Hypertrophic cardiomyopathy 14;C3279790:Atrial septal defect 3;C3279791:Sick sinus syndrome 3, susceptibility to;C3495498:Hypertrophic cardiomyopathy 1 (1)
-	-	1	Hypertrophic cardiomyopathy 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	11
DANN	Benign	0.95
PhyloP100		3.9
Mutation Taster		=90/10	polymorphism (auto)

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: rs28730770; hg19: chr14-23859590;