rs370765948

Variant names:

• chr2-178661797-G-A
• rs370765948
• NM_001267550.2:c.37247C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.37247C>T​(p.Ser12416Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S12416S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (5 hom., cov: 18)
  • Exomes 𝑓: 0.0014 (36 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.41
• Publications: 3 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

LOC124906100 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.011146307).
• BP6: Variant 2-178661797-G-A is Benign according to our data. Variant chr2-178661797-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 192171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00195 (292/150078) while in subpopulation NFE AF = 0.00258 (175/67788). AF 95% confidence interval is 0.00227. There are 5 homozygotes in GnomAd4. There are 134 alleles in the male GnomAd4 subpopulation. Median coverage is 18. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.37247C>T	p.Ser12416Leu	missense	Exon 180 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.34354+1169C>T		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.31573+1169C>T		intron	N/A	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.37247C>T	p.Ser12416Leu	missense	Exon 180 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.37247C>T	p.Ser12416Leu	missense	Exon 180 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.36971C>T	p.Ser12324Leu	missense	Exon 178 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 290 AN: 149962 Hom.: 4 Cov.: 18

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00178

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.00276

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00258

Gnomad OTH AF: 0.000971

GnomAD2 exomes AF: 0.000999 AC: 245 AN: 245308 AF XY: 0.000920

Gnomad AFR exome AF: 0.00118

Gnomad AMR exome AF: 0.000494

Gnomad ASJ exome AF: 0.000401

Gnomad EAS exome AF: 0.000560

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.00150

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00138 AC: 2013 AN: 1456722 Hom.: 36 Cov.: 31 AF XY: 0.00145 AC XY: 1051 AN XY: 724654

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

African (AFR) AF: 0.00106 AC: 35 AN: 33060

American (AMR) AF: 0.000650 AC: 29 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.000767 AC: 20 AN: 26090

East Asian (EAS) AF: 0.000530 AC: 21 AN: 39628

South Asian (SAS) AF: 0.000372 AC: 32 AN: 85926

European-Finnish (FIN) AF: 0.00210 AC: 112 AN: 53210

Middle Eastern (MID) AF: 0.000198 AC: 1 AN: 5046

European-Non Finnish (NFE) AF: 0.00152 AC: 1687 AN: 1109070

Other (OTH) AF: 0.00127 AC: 76 AN: 60070

⚠️ 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: 0.00195 AC: 292 AN: 150078 Hom.: 5 Cov.: 18 AF XY: 0.00183 AC XY: 134 AN XY: 73312

African (AFR) AF: 0.00130 AC: 52 AN: 40042

American (AMR) AF: 0.00178 AC: 27 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3462

East Asian (EAS) AF: 0.000977 AC: 5 AN: 5116

South Asian (SAS) AF: 0.000213 AC: 1 AN: 4704

European-Finnish (FIN) AF: 0.00276 AC: 29 AN: 10508

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

European-Non Finnish (NFE) AF: 0.00258 AC: 175 AN: 67788

Other (OTH) AF: 0.000961 AC: 2 AN: 2082

Alfa AF: 0.00191 Hom.: 1

ESP6500AA AF: 0.00402 AC: 7

ESP6500EA AF: 0.000502 AC: 2

ExAC AF: 0.00124 AC: 149

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTN: BP4, BS2

Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Early-onset myopathy with fatal cardiomyopathy Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Tibial muscular dystrophy Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Myopathy, myofibrillar, 9, with early respiratory failure Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.013
DANN	Benign	0.43
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.4
Vest4		0.047
MVP		0.15
MPC		0.074
ClinPred		0.0026	T
GERP RS		-5.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs370765948; hg19: chr2-179526524;