chr14-23389064-G-C

Variant names:

• chr14-23389064-G-C
• rs57660219
• NM_002471.4:c.3979-9C>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.3979-9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (30 hom., cov: 0)
  • Exomes 𝑓: 0.0017 (21 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH6 NM_002471.4 intron
• Scores: Splicing: ADA: 0.001732
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.427
• 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=-0.73).
• BP6: Variant 14-23389064-G-C is Benign according to our data. Variant chr14-23389064-G-C is described in ClinVar as Benign. ClinVar VariationId is 239171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.226 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.3979-9C>G		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.3979-9C>G		intron	N/A	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.4012-9C>G		intron	N/A	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.3979-9C>G		intron	N/A	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 1547 AN: 67764 Hom.: 30 Cov.: 0

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000479

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.0121

GnomAD2 exomes AF: 0.00659 AC: 633 AN: 96074 AF XY: 0.00506

Gnomad AFR exome AF: 0.0948

Gnomad AMR exome AF: 0.00313

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000276

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000716

Gnomad OTH exome AF: 0.00156

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00169 AC: 1935 AN: 1146180 Hom.: 21 Cov.: 32 AF XY: 0.00142 AC XY: 811 AN XY: 569902

African (AFR) AF: 0.0516 AC: 1233 AN: 23916

American (AMR) AF: 0.00183 AC: 70 AN: 38212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17944

East Asian (EAS) AF: 0.000182 AC: 7 AN: 38530

South Asian (SAS) AF: 0.000402 AC: 29 AN: 72082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39018

Middle Eastern (MID) AF: 0.000645 AC: 3 AN: 4648

European-Non Finnish (NFE) AF: 0.000544 AC: 470 AN: 864710

Other (OTH) AF: 0.00261 AC: 123 AN: 47120

GnomAD4 genome AF: 0.0229 AC: 1553 AN: 67778 Hom.: 30 Cov.: 0 AF XY: 0.0223 AC XY: 751 AN XY: 33668

African (AFR) AF: 0.236 AC: 1465 AN: 6218

American (AMR) AF: 0.00497 AC: 44 AN: 8850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1592

East Asian (EAS) AF: 0.000480 AC: 2 AN: 4164

South Asian (SAS) AF: 0.00 AC: 0 AN: 2602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 140

European-Non Finnish (NFE) AF: 0.000853 AC: 31 AN: 36334

Other (OTH) AF: 0.0120 AC: 11 AN: 920

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0113

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 14 (1)
-	-	1	MYH6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	4.0
DANN	Benign	0.82
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0017
dbscSNV1_RF	Benign	0.036
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: rs57660219; hg19: chr14-23858273;