NM_002471.4:c.3979-8delC

Variant names:

• chr14-23389062-AG-A
• rs193922652
• NM_002471.4:c.3979-8delC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_002471.4(MYH6):​c.3979-8delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 0.35 (8254 hom., cov: 0)
  • Exomes 𝑓: 0.31 (26611 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH6 NM_002471.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:9 O:2
• Conservation: PhyloP100: 0.275
• Publications: 5 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.

• BP6: Variant 14-23389062-AG-A is Benign according to our data. Variant chr14-23389062-AG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36628.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.605 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.3979-8delC		splice_region 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.3979-8delC		splice_region intron	N/A	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.4012-8delC		splice_region intron	N/A	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.3979-8delC		splice_region intron	N/A	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.353 AC: 40782 AN: 115534 Hom.: 8236 Cov.: 0

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.260

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.338

GnomAD2 exomes AF: 0.320 AC: 44689 AN: 139674 AF XY: 0.320

Gnomad AFR exome AF: 0.610

Gnomad AMR exome AF: 0.262

Gnomad ASJ exome AF: 0.283

Gnomad EAS exome AF: 0.271

Gnomad FIN exome AF: 0.283

Gnomad NFE exome AF: 0.274

Gnomad OTH exome AF: 0.288

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.308 AC: 297903 AN: 966060 Hom.: 26611 Cov.: 0 AF XY: 0.307 AC XY: 147489 AN XY: 479754

African (AFR) AF: 0.616 AC: 18501 AN: 30024

American (AMR) AF: 0.250 AC: 6265 AN: 25092

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 4699 AN: 17628

East Asian (EAS) AF: 0.260 AC: 5114 AN: 19658

South Asian (SAS) AF: 0.350 AC: 21151 AN: 60378

European-Finnish (FIN) AF: 0.254 AC: 7748 AN: 30466

Middle Eastern (MID) AF: 0.314 AC: 1225 AN: 3902

European-Non Finnish (NFE) AF: 0.298 AC: 219961 AN: 737912

Other (OTH) AF: 0.323 AC: 13239 AN: 41000

GnomAD4 genome AF: 0.353 AC: 40854 AN: 115646 Hom.: 8254 Cov.: 0 AF XY: 0.345 AC XY: 19621 AN XY: 56834

African (AFR) AF: 0.612 AC: 23773 AN: 38846

American (AMR) AF: 0.236 AC: 2658 AN: 11280

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 609 AN: 2598

East Asian (EAS) AF: 0.157 AC: 477 AN: 3032

South Asian (SAS) AF: 0.317 AC: 1085 AN: 3426

European-Finnish (FIN) AF: 0.179 AC: 1265 AN: 7078

Middle Eastern (MID) AF: 0.264 AC: 64 AN: 242

European-Non Finnish (NFE) AF: 0.217 AC: 10173 AN: 46880

Other (OTH) AF: 0.337 AC: 535 AN: 1588

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (6)
-	-	2	Cardiomyopathy (2)
-	1	-	Atrial septal defect (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated Cardiomyopathy, Dominant (1)
-	1	-	Hypertrophic cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 14 (1)
-	-	-	Hypertrophic cardiomyopathy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.28
Mutation Taster		=100/0	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: rs193922652; hg19: chr14-23858271; COSMIC: COSV62452355; COSMIC: COSV62452355;