chr15-43600610-T-G

Variant names:

• chr15-43600610-T-G
• rs2860666
• NM_153700.2:c.4917A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_153700.2(STRC):​c.4917A>C​(p.Leu1639Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 151,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0019 (29 hom.)
  • Failed GnomAD Quality Control
• Consequence: STRC NM_153700.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0820
• Publications: 0 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 15-43600610-T-G is Benign according to our data. Variant chr15-43600610-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 805531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.082 with no splicing effect.

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.4917A>C	p.Leu1639Leu	synonymous	Exon 26 of 29	NP_714544.1	Q7RTU9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRC	ENST00000450892.7	TSL:5 MANE Select	c.4917A>C	p.Leu1639Leu	synonymous	Exon 26 of 29	ENSP00000401513.2	Q7RTU9
	STRC	ENST00000440125.5	TSL:1	n.*2709A>C		non_coding_transcript_exon	Exon 25 of 28	ENSP00000394866.1	E7EPM8
	STRC	ENST00000440125.5	TSL:1	n.*2709A>C		3_prime_UTR	Exon 25 of 28	ENSP00000394866.1	E7EPM8

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 265 AN: 151156 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000558

Gnomad AMI AF: 0.00225

Gnomad AMR AF: 0.00191

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00343

Gnomad FIN AF: 0.0000949

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00278

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00118 AC: 297 AN: 251056 AF XY: 0.00120

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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00185 AC: 2696 AN: 1454202 Hom.: 29 Cov.: 32 AF XY: 0.00180 AC XY: 1304 AN XY: 722832

⚠️ 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: 0.000725 AC: 61 AN: 84142

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53394

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

European-Non Finnish (NFE) AF: 0.00218 AC: 2417 AN: 1106876

Other (OTH) AF: 0.00173 AC: 104 AN: 60150

⚠️ 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: 0.00175 AC: 264 AN: 151276 Hom.: 0 Cov.: 26 AF XY: 0.00151 AC XY: 112 AN XY: 73938

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

African (AFR) AF: 0.000556 AC: 23 AN: 41354

American (AMR) AF: 0.00190 AC: 29 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00321 AC: 15 AN: 4666

European-Finnish (FIN) AF: 0.0000949 AC: 1 AN: 10534

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

European-Non Finnish (NFE) AF: 0.00278 AC: 188 AN: 67572

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

⚠️ 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: 0.00167 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal recessive nonsyndromic hearing loss 16 (1)
-	-	1	Autosomal recessive nonsyndromic hearing loss 16;C1970187:Deafness-infertility syndrome;C2751811:Spermatogenic failure 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.9
DANN	Benign	0.66
PhyloP100		0.082
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs2860666; hg19: chr15-43892808;