14-23389062-AGGG-AG

Variant names:

• chr14-23389062-AGG-A
• rs193922652
• NM_002471.4:c.3979-9_3979-8delCC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002471.4(MYH6):​c.3979-9_3979-8delCC 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (763 hom., cov: 0)
  • Exomes 𝑓: 0.14 (11301 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH6 NM_002471.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• 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 -16 ACMG points.

• BP6: Variant 14-23389062-AGG-A is Benign according to our data. Variant chr14-23389062-AGG-A is described in ClinVar as Benign. ClinVar VariationId is 220788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.164 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.3979-9_3979-8delCC		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.3979-9_3979-8delCC		splice_region intron	N/A	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.4012-9_4012-8delCC		splice_region intron	N/A	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.3979-9_3979-8delCC		splice_region intron	N/A	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 14951 AN: 115620 Hom.: 761 Cov.: 0

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.0912

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.000657

Gnomad SAS AF: 0.0461

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.0969

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.121

GnomAD2 exomes AF: 0.122 AC: 17018 AN: 139674 AF XY: 0.120

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.0826

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.000548

Gnomad FIN exome AF: 0.132

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.130

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.141 AC: 149380 AN: 1057912 Hom.: 11301 AF XY: 0.137 AC XY: 72412 AN XY: 527248

African (AFR) AF: 0.112 AC: 3379 AN: 30300

American (AMR) AF: 0.0667 AC: 1970 AN: 29532

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 3486 AN: 19368

East Asian (EAS) AF: 0.000180 AC: 5 AN: 27780

South Asian (SAS) AF: 0.0497 AC: 3254 AN: 65464

European-Finnish (FIN) AF: 0.107 AC: 3761 AN: 35006

Middle Eastern (MID) AF: 0.0937 AC: 393 AN: 4194

European-Non Finnish (NFE) AF: 0.159 AC: 127150 AN: 801160

Other (OTH) AF: 0.133 AC: 5982 AN: 45108

GnomAD4 genome AF: 0.129 AC: 14958 AN: 115736 Hom.: 763 Cov.: 0 AF XY: 0.125 AC XY: 7118 AN XY: 56878

African (AFR) AF: 0.109 AC: 4258 AN: 38888

American (AMR) AF: 0.0912 AC: 1030 AN: 11288

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 505 AN: 2596

East Asian (EAS) AF: 0.000659 AC: 2 AN: 3034

South Asian (SAS) AF: 0.0460 AC: 158 AN: 3432

European-Finnish (FIN) AF: 0.122 AC: 863 AN: 7100

Middle Eastern (MID) AF: 0.0992 AC: 24 AN: 242

European-Non Finnish (NFE) AF: 0.167 AC: 7846 AN: 46890

Other (OTH) AF: 0.119 AC: 190 AN: 1590

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 14 (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)		0.020		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;