14-23390401-C-T

Variant names:

• chr14-23390401-C-T
• rs28730771
• NM_002471.4:c.3388G>A

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.3388G>A​(p.Ala1130Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,609,018 control chromosomes in the GnomAD database, including 7,777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1130S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.089 (591 hom., cov: 31)
  • Exomes 𝑓: 0.12 (7186 hom.)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.899
• Publications: 24 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=0.0033628345).
• BP6: Variant 14-23390401-C-T is Benign according to our data. Variant chr14-23390401-C-T is described in ClinVar as Benign. ClinVar VariationId is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.121 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.3388G>A	p.Ala1130Thr	missense	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.3388G>A	p.Ala1130Thr	missense	Exon 26 of 39	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.3421G>A	p.Ala1141Thr	missense	Exon 26 of 39	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.3388G>A	p.Ala1130Thr	missense	Exon 26 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.0887 AC: 13458 AN: 151666 Hom.: 588 Cov.: 31

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.0692

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0952

Gnomad EAS AF: 0.0714

Gnomad SAS AF: 0.0686

Gnomad FIN AF: 0.0916

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.0947 AC: 23065 AN: 243682 AF XY: 0.0958

Gnomad AFR exome AF: 0.0216

Gnomad AMR exome AF: 0.0950

Gnomad ASJ exome AF: 0.0879

Gnomad EAS exome AF: 0.0671

Gnomad FIN exome AF: 0.0819

Gnomad NFE exome AF: 0.119

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.117 AC: 170393 AN: 1457236 Hom.: 7186 Cov.: 37 AF XY: 0.115 AC XY: 83702 AN XY: 724798

African (AFR) AF: 0.0221 AC: 737 AN: 33382

American (AMR) AF: 0.0976 AC: 4339 AN: 44470

Ashkenazi Jewish (ASJ) AF: 0.0937 AC: 2444 AN: 26076

East Asian (EAS) AF: 0.0752 AC: 2976 AN: 39568

South Asian (SAS) AF: 0.0668 AC: 5743 AN: 85986

European-Finnish (FIN) AF: 0.0806 AC: 4133 AN: 51258

Middle Eastern (MID) AF: 0.109 AC: 617 AN: 5650

European-Non Finnish (NFE) AF: 0.129 AC: 143357 AN: 1110588

Other (OTH) AF: 0.100 AC: 6047 AN: 60258

GnomAD4 genome AF: 0.0887 AC: 13467 AN: 151782 Hom.: 591 Cov.: 31 AF XY: 0.0861 AC XY: 6389 AN XY: 74212

African (AFR) AF: 0.0259 AC: 1073 AN: 41458

American (AMR) AF: 0.109 AC: 1664 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.0952 AC: 330 AN: 3468

East Asian (EAS) AF: 0.0712 AC: 368 AN: 5172

South Asian (SAS) AF: 0.0695 AC: 333 AN: 4790

European-Finnish (FIN) AF: 0.0916 AC: 968 AN: 10566

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.124 AC: 8382 AN: 67808

Other (OTH) AF: 0.119 AC: 249 AN: 2096

Alfa AF: 0.111 Hom.: 1275

Bravo AF: 0.0906

TwinsUK AF: 0.138 AC: 513

ALSPAC AF: 0.129 AC: 499

ExAC AF: 0.0910 AC: 11012

Asia WGS AF: 0.0760 AC: 263 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.050
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.90
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.40
Sift	Benign	0.33	T
Sift4G	Benign	0.12	T
Polyphen		0.89	P
Vest4		0.47
MPC		2.8
ClinPred		0.037	T
GERP RS		3.4
Varity_R		0.033
gMVP		0.52
Mutation Taster		=86/14	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: rs28730771; hg19: chr14-23859610; COSMIC: COSV62447907; COSMIC: COSV62447907;