rs377674360

Variant names:

• chr15-43604422-A-G
• rs377674360
• NM_153700.2:c.4157T>C

Your query was ambiguous. Multiple possible variants found:

• chr15-43604422-A-G
• chr15-43604422-A-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 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. 12/20 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:2 B:1
• Conservation: PhyloP100: 3.22
• 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 -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_153700.2
• 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 VariationId is 227967.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 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 GnomAdExome4. There are 220 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.4157T>C	p.Val1386Ala	missense	Exon 21 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.4157T>C	p.Val1386Ala	missense	Exon 21 of 29	ENSP00000401513.2	Q7RTU9
	STRC	ENST00000440125.5	TSL:1	n.*1949T>C		non_coding_transcript_exon	Exon 20 of 28	ENSP00000394866.1	E7EPM8
	STRC	ENST00000440125.5	TSL:1	n.*1949T>C		3_prime_UTR	Exon 20 of 28	ENSP00000394866.1	E7EPM8

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

GnomAD2 exomes AF: 0.00148 AC: 278 AN: 187272 AF XY: 0.00124

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 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

African (AFR) AF: 0.000545 AC: 18 AN: 33002

American (AMR) AF: 0.00823 AC: 337 AN: 40928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25618

East Asian (EAS) AF: 0.00236 AC: 92 AN: 39026

South Asian (SAS) AF: 0.0000479 AC: 4 AN: 83590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51626

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5654

European-Non Finnish (NFE) AF: 0.0000146 AC: 16 AN: 1094528

Other (OTH) AF: 0.000659 AC: 39 AN: 59190

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

African (AFR) AF: 0.000580 AC: 24 AN: 41366

American (AMR) AF: 0.00499 AC: 76 AN: 15228

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

East Asian (EAS) AF: 0.00387 AC: 20 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

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

European-Non Finnish (NFE) AF: 0.0000884 AC: 6 AN: 67882

Other (OTH) AF: 0.000953 AC: 2 AN: 2098

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0097	T
MetaSVM	Uncertain	-0.27	T
PhyloP100		3.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		0.37	B
Vest4		0.60
MVP		0.74
ClinPred		0.057	T
GERP RS		5.3
Varity_R		0.16
gMVP		0.39
Mutation Taster		=97/3	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: rs377674360; hg19: chr15-43896620;