14-23389060-GGA-G

Variant names:

• chr14-23389060-GGA-G
• rs796313537
• NM_002471.4:c.3979-7_3979-6delTC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_002471.4(MYH6):​c.3979-7_3979-6delTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 121,160 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00062 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH6 NM_002471.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -0.131
• Publications: 0 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):

• hypertrophic cardiomyopathy 14

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
• 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: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 14-23389060-GGA-G is Benign according to our data. Variant chr14-23389060-GGA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44498.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000289 (35/121160) while in subpopulation AFR AF = 0.00151 (29/19236). AF 95% confidence interval is 0.00108. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 35 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	NM_002471.4	MANE Select	c.3979-7_3979-6delTC		splice_region intron	N/A	NP_002462.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	ENST00000405093.9	TSL:5 MANE Select	c.3979-7_3979-6delTC		splice_region intron	N/A	ENSP00000386041.3
	MYH6	ENST00000968262.1		c.4012-7_4012-6delTC		splice_region intron	N/A	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.3979-7_3979-6delTC		splice_region intron	N/A	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 35 AN: 121102 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000712

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000299

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000320

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000542 AC: 10 AN: 184396 AF XY: 0.0000396

Gnomad AFR exome AF: 0.000848

Gnomad AMR exome AF: 0.0000664

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000577

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000118

Gnomad OTH exome AF: 0.000220

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000618 AC: 880 AN: 1424558 Hom.: 0 AF XY: 0.000608 AC XY: 430 AN XY: 706840

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000121 AC: 4 AN: 33090

American (AMR) AF: 0.0000461 AC: 2 AN: 43424

Ashkenazi Jewish (ASJ) AF: 0.000560 AC: 14 AN: 24980

East Asian (EAS) AF: 0.0000763 AC: 3 AN: 39336

South Asian (SAS) AF: 0.0000594 AC: 5 AN: 84156

European-Finnish (FIN) AF: 0.0000408 AC: 2 AN: 48962

Middle Eastern (MID) AF: 0.000540 AC: 3 AN: 5560

European-Non Finnish (NFE) AF: 0.000749 AC: 813 AN: 1086166

Other (OTH) AF: 0.000577 AC: 34 AN: 58884

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000289 AC: 35 AN: 121160 Hom.: 0 Cov.: 26 AF XY: 0.000319 AC XY: 19 AN XY: 59560

African (AFR) AF: 0.00151 AC: 29 AN: 19236

American (AMR) AF: 0.0000710 AC: 1 AN: 14076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3084

East Asian (EAS) AF: 0.00 AC: 0 AN: 5080

South Asian (SAS) AF: 0.00 AC: 0 AN: 4316

European-Finnish (FIN) AF: 0.000299 AC: 3 AN: 10048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.0000320 AC: 2 AN: 62468

Other (OTH) AF: 0.00 AC: 0 AN: 1780

Alfa AF: 0.0000843 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 14 (1)
-	-	1	MYH6-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.13
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs796313537; hg19: chr14-23858269;