rs377674360

Positions:

• chr15-43604422-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_153700.2(STRC):​c.4157T>C​(p.Val1386Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,584,908 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00084 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00035 (10 hom.)
• Consequence: STRC NM_153700.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.22

Genes affected

STRC (HGNC:16035): (stereocilin) This gene encodes a protein that is associated with the hair bundle of the sensory hair cells in the inner ear. The hair bundle is composed of stiff microvilli called stereocilia and is involved with mechanoreception of sound waves. This gene is part of a tandem duplication on chromosome 15; the second copy is a pseudogene. Mutations in this gene cause autosomal recessive non-syndromic deafness. [provided by RefSeq, Jul 2008]

CKMT1B (HGNC:1995): (creatine kinase, mitochondrial 1B) Mitochondrial creatine (MtCK) kinase is responsible for the transfer of high energy phosphate from mitochondria to the cytosolic carrier, creatine. It belongs to the creatine kinase isoenzyme family. It exists as two isoenzymes, sarcomeric MtCK and ubiquitous MtCK, encoded by separate genes. Mitochondrial creatine kinase occurs in two different oligomeric forms: dimers and octamers, in contrast to the exclusively dimeric cytosolic creatine kinase isoenzymes. Many malignant cancers with poor prognosis have shown overexpression of ubiquitous mitochondrial creatine kinase; this may be related to high energy turnover and failure to eliminate cancer cells via apoptosis. Ubiquitous mitochondrial creatine kinase has 80% homology with the coding exons of sarcomeric mitochondrial creatine kinase. Two genes located near each other on chromosome 15 have been identified which encode identical mitochondrial creatine kinase proteins. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009735584).
• BP6: Variant 15-43604422-A-G is Benign according to our data. Variant chr15-43604422-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227967.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000354 (507/1433162) while in subpopulation AMR AF= 0.00823 (337/40928). AF 95% confidence interval is 0.00751. There are 10 homozygotes in gnomad4_exome. There are 220 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STRC	NM_153700.2	c.4157T>C	p.Val1386Ala	missense_variant	21/29	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7	c.4157T>C	p.Val1386Ala	missense_variant	21/29	5	NM_153700.2	ENSP00000401513.2

Frequencies

GnomAD3 genomes AF: 0.000824 AC: 125 AN: 151628 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000582

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00480

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00387

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000884

Gnomad OTH AF: 0.000963

GnomAD3 exomes AF: 0.00148 AC: 278 AN: 187272 Hom.: 5 AF XY: 0.00124 AC XY: 125 AN XY: 100630

Gnomad AFR exome AF: 0.000662

Gnomad AMR exome AF: 0.00770

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00291

Gnomad SAS exome AF: 0.0000387

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000655

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.000354 AC: 507 AN: 1433162 Hom.: 10 Cov.: 32 AF XY: 0.000310 AC XY: 220 AN XY: 710496

Gnomad4 AFR exome AF: 0.000545

Gnomad4 AMR exome AF: 0.00823

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00236

Gnomad4 SAS exome AF: 0.0000479

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000146

Gnomad4 OTH exome AF: 0.000659

GnomAD4 genome AF: 0.000844 AC: 128 AN: 151746 Hom.: 2 Cov.: 31 AF XY: 0.00105 AC XY: 78 AN XY: 74134

Gnomad4 AFR AF: 0.000580

Gnomad4 AMR AF: 0.00499

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000884

Gnomad4 OTH AF: 0.000953

Alfa AF: 0.000470 Hom.: 1

Bravo AF: 0.00137

ESP6500AA AF: 0.000463 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000852 AC: 101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 23, 2017

The V1386A variant in the STRC gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. It is reported as likely benign in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000270870.1; Landrum et al., 2015). The V1386A variant is observed in 6/694 (0.86%) alleles from individuals of mixed American background in the 1000 Genomes Project and in 76/78406 (0.097%) alleles from individuals undergoing testing at GeneDx who were not reported to have features of DFNB16, including one homozygous individual (1000 Genomes Consortium et al., 2015). The V1386A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V1386A as a variant of uncertain significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 26, 2015

p.Val1386Ala in exon 21 of STRC: This variant is not expected to have clinical s ignificance because it has been identified in 2.6% (32/1250) of Latino chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs377674360). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.68	T;T
MetaRNN	Benign	0.0097	T;T
MetaSVM	Uncertain	-0.27	T
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.37	B;D
Vest4		0.60
MVP		0.74
ClinPred		0.057	T
GERP RS		5.3
Varity_R		0.16
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs377674360; hg19: chr15-43896620;