14-23389063-G-C

Variant names:

• chr14-23389063-G-C
• rs555976716
• NM_002471.4:c.3979-8C>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.3979-8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (7 hom., cov: 0)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: MYH6 NM_002471.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001091
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.275
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 14-23389063-G-C is Benign according to our data. Variant chr14-23389063-G-C is described in ClinVar as Benign. ClinVar VariationId is 414321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0959 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.3979-8C>G		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.3979-8C>G		splice_region intron	N/A	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.4012-8C>G		splice_region intron	N/A	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.3979-8C>G		splice_region intron	N/A	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.00925 AC: 601 AN: 64970 Hom.: 7 Cov.: 0

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00258

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000493

Gnomad SAS AF: 0.000401

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000852

Gnomad OTH AF: 0.00814

GnomAD2 exomes AF: 0.00155 AC: 236 AN: 152678 AF XY: 0.00125

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.000175

Gnomad EAS exome AF: 0.000756

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00178

GnomAD4 exome AF: 0.00135 AC: 583 AN: 431214 Hom.: 3 Cov.: 0 AF XY: 0.00118 AC XY: 249 AN XY: 210794

African (AFR) AF: 0.0450 AC: 432 AN: 9590

American (AMR) AF: 0.00278 AC: 36 AN: 12930

Ashkenazi Jewish (ASJ) AF: 0.000526 AC: 3 AN: 5700

East Asian (EAS) AF: 0.00214 AC: 27 AN: 12640

South Asian (SAS) AF: 0.000164 AC: 4 AN: 24332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1852

European-Non Finnish (NFE) AF: 0.000113 AC: 38 AN: 335064

Other (OTH) AF: 0.00258 AC: 43 AN: 16680

GnomAD4 genome AF: 0.00924 AC: 600 AN: 64956 Hom.: 7 Cov.: 0 AF XY: 0.00866 AC XY: 278 AN XY: 32114

African (AFR) AF: 0.103 AC: 565 AN: 5492

American (AMR) AF: 0.00257 AC: 22 AN: 8544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1556

East Asian (EAS) AF: 0.000495 AC: 2 AN: 4040

South Asian (SAS) AF: 0.000402 AC: 1 AN: 2486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 124

European-Non Finnish (NFE) AF: 0.0000852 AC: 3 AN: 35204

Other (OTH) AF: 0.00808 AC: 7 AN: 866

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Hypertrophic cardiomyopathy 14 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.2
DANN	Benign	0.88
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.028
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: rs555976716; hg19: chr14-23858272;