2-178751204-C-G

Variant names:

• chr2-178751204-C-G
• rs922985
• NM_001267550.2:c.11311+1920G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133379.5(TTN):​c.11196G>C​(p.Leu3732Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 1,609,690 control chromosomes in the GnomAD database, including 797,963 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (72577 hom., cov: 32)
  • Exomes 𝑓: 1.0 (725386 hom.)
• Consequence: TTN NM_133379.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.174
• Publications: 25 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=8.2521825E-7).
• BP6: Variant 2-178751204-C-G is Benign according to our data. Variant chr2-178751204-C-G is described in ClinVar as Benign. ClinVar VariationId is 47735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133379.5. 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
	TTN	NM_001267550.2	MANE Select	c.11311+1920G>C		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_133379.5		c.11196G>C	p.Leu3732Phe	missense	Exon 46 of 46	NP_596870.2	Q8WZ42-6
	TTN	NM_001256850.1		c.10360+1920G>C		intron	N/A	NP_001243779.1	Q8WZ42-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.11311+1920G>C		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.11311+1920G>C		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.11035+1920G>C		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.977 AC: 148363 AN: 151920 Hom.: 72550 Cov.: 32

Gnomad AFR AF: 0.918

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.994

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.981

GnomAD2 exomes AF: 0.994 AC: 245536 AN: 246976 AF XY: 0.996

Gnomad AFR exome AF: 0.920

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.997

GnomAD4 exome AF: 0.998 AC: 1454075 AN: 1457652 Hom.: 725386 Cov.: 48 AF XY: 0.998 AC XY: 723135 AN XY: 724640

African (AFR) AF: 0.912 AC: 30359 AN: 33294

American (AMR) AF: 0.996 AC: 44063 AN: 44218

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 25960 AN: 25960

East Asian (EAS) AF: 1.00 AC: 39570 AN: 39570

South Asian (SAS) AF: 1.00 AC: 85389 AN: 85414

European-Finnish (FIN) AF: 1.00 AC: 53248 AN: 53248

Middle Eastern (MID) AF: 0.996 AC: 5712 AN: 5734

European-Non Finnish (NFE) AF: 1.00 AC: 1109923 AN: 1110004

Other (OTH) AF: 0.994 AC: 59851 AN: 60210

GnomAD4 genome AF: 0.976 AC: 148446 AN: 152038 Hom.: 72577 Cov.: 32 AF XY: 0.977 AC XY: 72655 AN XY: 74328

African (AFR) AF: 0.917 AC: 38076 AN: 41510

American (AMR) AF: 0.994 AC: 15149 AN: 15244

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3470 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5160 AN: 5160

South Asian (SAS) AF: 1.00 AC: 4814 AN: 4816

European-Finnish (FIN) AF: 1.00 AC: 10626 AN: 10626

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 67875 AN: 67894

Other (OTH) AF: 0.981 AC: 2072 AN: 2112

Alfa AF: 0.977 Hom.: 54328

Bravo AF: 0.973

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.920 AC: 4053

ESP6500EA AF: 0.999 AC: 8585

ExAC AF: 0.993 AC: 120419

Asia WGS AF: 0.992 AC: 3451 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.1
DANN	Benign	0.96
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	8.3e-7	T
MetaSVM	Benign	-0.97	T
PhyloP100		-0.17
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.14
Sift	Benign	0.10	T
Sift4G	Benign	0.70	T
Polyphen		0.0030	B
Vest4		0.028
MutPred		0.26		Loss of stability (P = 0.0961)
ClinPred		0.0017	T
GERP RS		3.9
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs922985; hg19: chr2-179615931; COSMIC: COSV59896745; COSMIC: COSV59896745;