chr14-23389065-G-A

Variant names:

• chr14-23389065-G-A
• rs28730768
• NM_002471.4:c.3979-10C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002471.4(MYH6):​c.3979-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000809 in 123,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000081 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000065 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH6 NM_002471.4 intron
• Scores: Splicing: ADA: 0.00008582
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.25
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 14-23389065-G-A is Benign according to our data. Variant chr14-23389065-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 414318.
• BS2: High AC in GnomAd4 at 10 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.3979-10C>T		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.3979-10C>T		intron	N/A	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.4012-10C>T		intron	N/A	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.3979-10C>T		intron	N/A	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.0000809 AC: 10 AN: 123556 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000902

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000752

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: 0.000113

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000472 AC: 9 AN: 190566 AF XY: 0.0000384

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000337

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000864

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000646 AC: 91 AN: 1408716 Hom.: 0 Cov.: 36 AF XY: 0.0000686 AC XY: 48 AN XY: 699528

African (AFR) AF: 0.00 AC: 0 AN: 32906

American (AMR) AF: 0.0000231 AC: 1 AN: 43206

Ashkenazi Jewish (ASJ) AF: 0.0000404 AC: 1 AN: 24730

East Asian (EAS) AF: 0.0000510 AC: 2 AN: 39238

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5490

European-Non Finnish (NFE) AF: 0.0000782 AC: 84 AN: 1073796

Other (OTH) AF: 0.0000343 AC: 2 AN: 58378

GnomAD4 genome AF: 0.0000809 AC: 10 AN: 123556 Hom.: 0 Cov.: 30 AF XY: 0.0000495 AC XY: 3 AN XY: 60612

African (AFR) AF: 0.0000902 AC: 3 AN: 33276

American (AMR) AF: 0.0000752 AC: 1 AN: 13290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2528

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53152

Other (OTH) AF: 0.00 AC: 0 AN: 1740

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 14 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.9
DANN	Benign	0.90
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000086
dbscSNV1_RF	Benign	0.046
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: rs28730768; hg19: chr14-23858274;