rs148091079

Variant names:

• chr14-23402483-C-T
• rs148091079
• NM_002471.4:c.1122G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-23402483-C-T
• chr14-23402483-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002471.4(MYH6):​c.1122G>A​(p.Ala374Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,613,398 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (6 hom.)
• Consequence: MYH6 NM_002471.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -9.30
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 14-23402483-C-T is Benign according to our data. Variant chr14-23402483-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-9.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00113 (171/151970) while in subpopulation AMR AF = 0.00196 (30/15284). AF 95% confidence interval is 0.00141. There are 1 homozygotes in GnomAd4. There are 96 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 171 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	NM_002471.4	MANE Select	c.1122G>A	p.Ala374Ala	synonymous	Exon 12 of 39	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.1122G>A	p.Ala374Ala	synonymous	Exon 12 of 39	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.1122G>A	p.Ala374Ala	synonymous	Exon 12 of 39	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.1122G>A	p.Ala374Ala	synonymous	Exon 12 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 151852 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00378

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00126 AC: 316 AN: 251280 AF XY: 0.00129

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00426

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00115 AC: 1683 AN: 1461428 Hom.: 6 Cov.: 33 AF XY: 0.00114 AC XY: 827 AN XY: 727024

African (AFR) AF: 0.000149 AC: 5 AN: 33460

American (AMR) AF: 0.000939 AC: 42 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86246

European-Finnish (FIN) AF: 0.00373 AC: 199 AN: 53306

Middle Eastern (MID) AF: 0.00109 AC: 6 AN: 5496

European-Non Finnish (NFE) AF: 0.00121 AC: 1345 AN: 1112002

Other (OTH) AF: 0.000961 AC: 58 AN: 60364

GnomAD4 genome AF: 0.00113 AC: 171 AN: 151970 Hom.: 1 Cov.: 31 AF XY: 0.00129 AC XY: 96 AN XY: 74282

African (AFR) AF: 0.000145 AC: 6 AN: 41446

American (AMR) AF: 0.00196 AC: 30 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00378 AC: 40 AN: 10574

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00134 AC: 91 AN: 67952

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.000733

EpiCase AF: 0.00147

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	5	not specified (5)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (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	-0.60
CADD	Benign	0.10
DANN	Benign	0.85
PhyloP100		-9.3
Mutation Taster		=97/3	polymorphism

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: rs148091079; hg19: chr14-23871692; COSMIC: COSV62452868;