rs12981413

Variant names:

• chr19-50260632-C-T
• rs12981413
• NM_001145809.2:c.2355-14C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001145809.2(MYH14):​c.2355-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 1,600,692 control chromosomes in the GnomAD database, including 157,937 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16467 hom., cov: 28)
  • Exomes 𝑓: 0.44 (141470 hom.)
• Consequence: MYH14 NM_001145809.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.110
• Publications: 11 publications found

Genes affected

MYH14 (HGNC:23212): (myosin heavy chain 14) This gene encodes a member of the myosin superfamily. The protein represents a conventional non-muscle myosin; it should not be confused with the unconventional myosin-14 (MYO14). Myosins are actin-dependent motor proteins with diverse functions including regulation of cytokinesis, cell motility, and cell polarity. Mutations in this gene result in one form of autosomal dominant hearing impairment. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

MYH14 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 4A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-50260632-C-T is Benign according to our data. Variant chr19-50260632-C-T is described in ClinVar as Benign. ClinVar VariationId is 44057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.582 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.2355-14C>T		intron_variant	Intron 19 of 42	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.2256-14C>T		intron_variant	Intron 18 of 41		NP_001070654.1
MYH14	NM_024729.4	c.2232-14C>T		intron_variant	Intron 17 of 40		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.2355-14C>T		intron_variant	Intron 19 of 42		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69507 AN: 151346 Hom.: 16445 Cov.: 28

Gnomad AFR AF: 0.467

Gnomad AMI AF: 0.560

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.536

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.440

GnomAD2 exomes AF: 0.454 AC: 111813 AN: 246398 AF XY: 0.442

Gnomad AFR exome AF: 0.468

Gnomad AMR exome AF: 0.662

Gnomad ASJ exome AF: 0.283

Gnomad EAS exome AF: 0.302

Gnomad FIN exome AF: 0.526

Gnomad NFE exome AF: 0.433

Gnomad OTH exome AF: 0.443

GnomAD4 exome AF: 0.437 AC: 633783 AN: 1449228 Hom.: 141470 Cov.: 31 AF XY: 0.434 AC XY: 313544 AN XY: 721636

African (AFR) AF: 0.467 AC: 15499 AN: 33172

American (AMR) AF: 0.649 AC: 28832 AN: 44424

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 7594 AN: 26028

East Asian (EAS) AF: 0.322 AC: 12731 AN: 39594

South Asian (SAS) AF: 0.388 AC: 33313 AN: 85882

European-Finnish (FIN) AF: 0.520 AC: 27645 AN: 53180

Middle Eastern (MID) AF: 0.338 AC: 1939 AN: 5744

European-Non Finnish (NFE) AF: 0.436 AC: 480672 AN: 1101234

Other (OTH) AF: 0.426 AC: 25558 AN: 59970

GnomAD4 genome AF: 0.459 AC: 69577 AN: 151464 Hom.: 16467 Cov.: 28 AF XY: 0.465 AC XY: 34387 AN XY: 73974

African (AFR) AF: 0.467 AC: 19257 AN: 41200

American (AMR) AF: 0.592 AC: 9013 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1019 AN: 3466

East Asian (EAS) AF: 0.311 AC: 1598 AN: 5140

South Asian (SAS) AF: 0.393 AC: 1881 AN: 4784

European-Finnish (FIN) AF: 0.536 AC: 5645 AN: 10524

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.437 AC: 29638 AN: 67840

Other (OTH) AF: 0.435 AC: 913 AN: 2098

Alfa AF: 0.426 Hom.: 2623

Bravo AF: 0.465

Asia WGS AF: 0.403 AC: 1398 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

2355-14C>T in Intron 19 of MYH14: This variant is not expected to have clinical significance because it has been identified in 45.9% (1652/3600) of African Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs12981413). -

Autosomal dominant nonsyndromic hearing loss 4A Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.6
DANN	Benign	0.64
PhyloP100		0.11
Mutation Taster		=99/1	polymorphism (auto)

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: rs12981413; hg19: chr19-50763889; COSMIC: COSV51812511; COSMIC: COSV51812511;