NM_002471.4:c.4651-12A>C

Variant names:

• chr14-23386635-T-G
• rs193922653
• NM_002471.4:c.4651-12A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002471.4(MYH6):​c.4651-12A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 144,334 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00057 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH6 NM_002471.4 intron
• Scores: Splicing: ADA: 0.000007133
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.865
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 14-23386635-T-G is Benign according to our data. Variant chr14-23386635-T-G is described in ClinVar as Benign. ClinVar VariationId is 36630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00395 (570/144334) while in subpopulation AFR AF = 0.0136 (539/39752). AF 95% confidence interval is 0.0126. There are 1 homozygotes in GnomAd4. There are 246 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 570 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.4651-12A>C		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.4651-12A>C		intron	N/A	ENSP00000386041.3

Frequencies

GnomAD3 genomes AF: 0.00396 AC: 571 AN: 144192 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00123

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000501

Gnomad FIN AF: 0.000221

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.0000456

Gnomad OTH AF: 0.00247

GnomAD2 exomes AF: 0.00100 AC: 244 AN: 243406 AF XY: 0.000700

Gnomad AFR exome AF: 0.0137

Gnomad AMR exome AF: 0.000641

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000913

Gnomad OTH exome AF: 0.000503

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000567 AC: 604 AN: 1066134 Hom.: 1 Cov.: 44 AF XY: 0.000480 AC XY: 258 AN XY: 537670

African (AFR) AF: 0.0163 AC: 417 AN: 25570

American (AMR) AF: 0.000751 AC: 30 AN: 39954

Ashkenazi Jewish (ASJ) AF: 0.000471 AC: 9 AN: 19094

East Asian (EAS) AF: 0.000157 AC: 4 AN: 25464

South Asian (SAS) AF: 0.0000386 AC: 3 AN: 77718

European-Finnish (FIN) AF: 0.000105 AC: 4 AN: 38076

Middle Eastern (MID) AF: 0.000443 AC: 2 AN: 4516

European-Non Finnish (NFE) AF: 0.000112 AC: 89 AN: 792848

Other (OTH) AF: 0.00107 AC: 46 AN: 42894

GnomAD4 genome AF: 0.00395 AC: 570 AN: 144334 Hom.: 1 Cov.: 31 AF XY: 0.00350 AC XY: 246 AN XY: 70228

African (AFR) AF: 0.0136 AC: 539 AN: 39752

American (AMR) AF: 0.00123 AC: 18 AN: 14688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3346

East Asian (EAS) AF: 0.00 AC: 0 AN: 4444

South Asian (SAS) AF: 0.000500 AC: 2 AN: 4002

European-Finnish (FIN) AF: 0.000221 AC: 2 AN: 9062

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.0000456 AC: 3 AN: 65860

Other (OTH) AF: 0.00244 AC: 5 AN: 2050

Alfa AF: 0.00225 Hom.: 0

ClinVar

ClinVar submissions as Germline

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)
-	-	1	not provided (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.7
DANN	Benign	0.40
PhyloP100		-0.86
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000071
dbscSNV1_RF	Benign	0.0
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: rs193922653; hg19: chr14-23855844;