rs365990

Variant names:

• chr14-23392602-A-G
• rs365990
• NM_002471.4:c.3302T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002471.4(MYH6):​c.3302T>C​(p.Val1101Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,604,286 control chromosomes in the GnomAD database, including 113,514 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1101M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.44 (14788 hom., cov: 26)
  • Exomes 𝑓: 0.36 (98726 hom.)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 3.37
• Publications: 94 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.2841323E-5).
• BP6: Variant 14-23392602-A-G is Benign according to our data. Variant chr14-23392602-A-G is described in ClinVar as Benign. ClinVar VariationId is 44480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.637 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.3302T>C	p.Val1101Ala	missense	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.3302T>C	p.Val1101Ala	missense	Exon 25 of 39	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.3335T>C	p.Val1112Ala	missense	Exon 25 of 39	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.3302T>C	p.Val1101Ala	missense	Exon 25 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.440 AC: 63492 AN: 144438 Hom.: 14737 Cov.: 26

Gnomad AFR AF: 0.643

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.471

Gnomad NFE AF: 0.374

Gnomad OTH AF: 0.440

GnomAD2 exomes AF: 0.337 AC: 84704 AN: 251460 AF XY: 0.336

Gnomad AFR exome AF: 0.627

Gnomad AMR exome AF: 0.234

Gnomad ASJ exome AF: 0.454

Gnomad EAS exome AF: 0.167

Gnomad FIN exome AF: 0.265

Gnomad NFE exome AF: 0.364

Gnomad OTH exome AF: 0.358

GnomAD4 exome AF: 0.360 AC: 525544 AN: 1459746 Hom.: 98726 Cov.: 42 AF XY: 0.358 AC XY: 260255 AN XY: 726358

African (AFR) AF: 0.638 AC: 21325 AN: 33432

American (AMR) AF: 0.245 AC: 10957 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 12056 AN: 26112

East Asian (EAS) AF: 0.149 AC: 5899 AN: 39664

South Asian (SAS) AF: 0.310 AC: 26733 AN: 86218

European-Finnish (FIN) AF: 0.272 AC: 14481 AN: 53330

Middle Eastern (MID) AF: 0.410 AC: 2359 AN: 5760

European-Non Finnish (NFE) AF: 0.369 AC: 409245 AN: 1110208

Other (OTH) AF: 0.373 AC: 22489 AN: 60308

GnomAD4 genome AF: 0.440 AC: 63597 AN: 144540 Hom.: 14788 Cov.: 26 AF XY: 0.440 AC XY: 30482 AN XY: 69328

African (AFR) AF: 0.643 AC: 25627 AN: 39848

American (AMR) AF: 0.375 AC: 4915 AN: 13114

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1595 AN: 3450

East Asian (EAS) AF: 0.178 AC: 841 AN: 4720

South Asian (SAS) AF: 0.313 AC: 1419 AN: 4540

European-Finnish (FIN) AF: 0.326 AC: 2798 AN: 8590

Middle Eastern (MID) AF: 0.465 AC: 118 AN: 254

European-Non Finnish (NFE) AF: 0.374 AC: 25100 AN: 67092

Other (OTH) AF: 0.449 AC: 912 AN: 2032

Alfa AF: 0.385 Hom.: 58826

Bravo AF: 0.433

TwinsUK AF: 0.373 AC: 1383

ALSPAC AF: 0.364 AC: 1403

ESP6500AA AF: 0.616 AC: 2712

ESP6500EA AF: 0.374 AC: 3214

ExAC AF: 0.346 AC: 42017

Asia WGS AF: 0.290 AC: 1008 AN: 3478

EpiCase AF: 0.382

EpiControl AF: 0.381

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.81
DEOGEN2	Benign	0.33	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.0048	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.000033	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.8	N
PhyloP100		3.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.022
MPC		0.42
ClinPred		0.0066	T
GERP RS		4.7
Varity_R		0.036
gMVP		0.24
Mutation Taster		=99/1	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: rs365990; hg19: chr14-23861811; COSMIC: COSV62450867; COSMIC: COSV62450867;