rs434273

Variant names:

• chr14-23403457-T-C
• rs434273
• NM_002471.4:c.800-11A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-23403457-T-C
• chr14-23403457-T-A
• chr14-23403457-T-G

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.800-11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 1,611,044 control chromosomes in the GnomAD database, including 472,572 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50513 hom., cov: 31)
  • Exomes 𝑓: 0.76 (422059 hom.)
• Consequence: MYH6 NM_002471.4 intron
• Scores: Splicing: ADA: 0.000006417
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.255
• Publications: 11 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 (BayesDel_noAF=-0.9).
• BP6: Variant 14-23403457-T-C is Benign according to our data. Variant chr14-23403457-T-C is described in ClinVar as Benign. ClinVar VariationId is 44544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.942 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.800-11A>G		intron	N/A	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.800-11A>G		intron	N/A	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.800-11A>G		intron	N/A	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.800-11A>G		intron	N/A	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.810 AC: 122907 AN: 151762 Hom.: 50460 Cov.: 31

Gnomad AFR AF: 0.950

Gnomad AMI AF: 0.685

Gnomad AMR AF: 0.768

Gnomad ASJ AF: 0.835

Gnomad EAS AF: 0.667

Gnomad SAS AF: 0.672

Gnomad FIN AF: 0.762

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.762

Gnomad OTH AF: 0.807

GnomAD2 exomes AF: 0.753 AC: 189352 AN: 251298 AF XY: 0.749

Gnomad AFR exome AF: 0.953

Gnomad AMR exome AF: 0.722

Gnomad ASJ exome AF: 0.844

Gnomad EAS exome AF: 0.676

Gnomad FIN exome AF: 0.750

Gnomad NFE exome AF: 0.760

Gnomad OTH exome AF: 0.764

GnomAD4 exome AF: 0.759 AC: 1107283 AN: 1459164 Hom.: 422059 Cov.: 38 AF XY: 0.756 AC XY: 549038 AN XY: 726118

African (AFR) AF: 0.958 AC: 32039 AN: 33428

American (AMR) AF: 0.731 AC: 32675 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.842 AC: 21984 AN: 26124

East Asian (EAS) AF: 0.709 AC: 28136 AN: 39680

South Asian (SAS) AF: 0.673 AC: 58047 AN: 86198

European-Finnish (FIN) AF: 0.748 AC: 39947 AN: 53400

Middle Eastern (MID) AF: 0.821 AC: 4733 AN: 5762

European-Non Finnish (NFE) AF: 0.760 AC: 843633 AN: 1109542

Other (OTH) AF: 0.764 AC: 46089 AN: 60316

GnomAD4 genome AF: 0.810 AC: 123023 AN: 151880 Hom.: 50513 Cov.: 31 AF XY: 0.807 AC XY: 59835 AN XY: 74190

African (AFR) AF: 0.950 AC: 39377 AN: 41446

American (AMR) AF: 0.768 AC: 11725 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.835 AC: 2897 AN: 3468

East Asian (EAS) AF: 0.667 AC: 3425 AN: 5132

South Asian (SAS) AF: 0.673 AC: 3227 AN: 4798

European-Finnish (FIN) AF: 0.762 AC: 8038 AN: 10552

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.762 AC: 51767 AN: 67898

Other (OTH) AF: 0.809 AC: 1702 AN: 2104

Alfa AF: 0.795 Hom.: 26261

Bravo AF: 0.816

Asia WGS AF: 0.701 AC: 2433 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	Hypertrophic cardiomyopathy 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.0
DANN	Benign	0.44
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000064
dbscSNV1_RF	Benign	0.0
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: rs434273; hg19: chr14-23872666; COSMIC: COSV62452535;