rs2920791

Variant names:

• chr15-43600609-G-A
• rs2920791
• NM_153700.2:c.4918C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PS1_Moderate BP4_Moderate BS2

The NM_153700.2(STRC):​c.4918C>T​(p.Leu1640Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,606,082 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1640R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0018 (29 hom.)
• Consequence: STRC NM_153700.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:2
• Conservation: PhyloP100: 2.79
• Publications: 4 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PS1: Transcript NM_153700.2 (STRC) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08820775).
• BS2: High Homozygotes in GnomAdExome4 at 29 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153700.2. 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
	STRC	NM_153700.2	MANE Select	c.4918C>T	p.Leu1640Phe	missense	Exon 26 of 29	NP_714544.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRC	ENST00000450892.7	TSL:5 MANE Select	c.4918C>T	p.Leu1640Phe	missense	Exon 26 of 29	ENSP00000401513.2
	STRC	ENST00000440125.5	TSL:1	n.*2710C>T		non_coding_transcript_exon	Exon 25 of 28	ENSP00000394866.1
	STRC	ENST00000440125.5	TSL:1	n.*2710C>T		3_prime_UTR	Exon 25 of 28	ENSP00000394866.1

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 265 AN: 151408 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000557

Gnomad AMI AF: 0.00335

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00362

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00118 AC: 296 AN: 251078 AF XY: 0.00119

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00200

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00185 AC: 2686 AN: 1454554 Hom.: 29 Cov.: 32 AF XY: 0.00180 AC XY: 1300 AN XY: 723052

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000329 AC: 11 AN: 33438

American (AMR) AF: 0.00208 AC: 93 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.000701 AC: 59 AN: 84196

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53396

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5720

European-Non Finnish (NFE) AF: 0.00217 AC: 2408 AN: 1107168

Other (OTH) AF: 0.00175 AC: 105 AN: 60154

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00174 AC: 264 AN: 151528 Hom.: 0 Cov.: 26 AF XY: 0.00148 AC XY: 110 AN XY: 74084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000555 AC: 23 AN: 41434

American (AMR) AF: 0.00190 AC: 29 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00341 AC: 16 AN: 4692

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00275 AC: 186 AN: 67646

Other (OTH) AF: 0.00237 AC: 5 AN: 2106

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000428 Hom.: 0

ExAC AF: 0.00108 AC: 131

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	-	Autosomal recessive nonsyndromic hearing loss 16 (3)
-	1	2	not provided (3)
-	1	-	STRC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.088	T
MetaSVM	Uncertain	-0.091	T
PhyloP100		2.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.30
Sift	Benign	0.079	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.95	P
Vest4		0.30
MVP		0.77
ClinPred		0.068	T
GERP RS		4.8
Varity_R		0.069
gMVP		0.49
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2920791; hg19: chr15-43892807; COSMIC: COSV55853281; COSMIC: COSV55853281;