chr2-178774570-C-T

Variant names:

• chr2-178774570-C-T
• rs3816781
• NM_001267550.2:c.6791-97G>A

Variant summary

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

The NM_001267550.2(TTN):​c.6791-97G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.971 in 1,162,060 control chromosomes in the GnomAD database, including 549,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (66197 hom., cov: 32)
  • Exomes 𝑓: 0.98 (482920 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.466
• Publications: 4 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 (BayesDel_noAF=-0.79).
• BP6: Variant 2-178774570-C-T is Benign according to our data. Variant chr2-178774570-C-T is described in ClinVar as Benign. ClinVar VariationId is 1275365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.6791-97G>A		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.6791-97G>A		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.6791-97G>A		intron	N/A	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.6791-97G>A		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.6791-97G>A		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.6515-97G>A		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.929 AC: 141325 AN: 152130 Hom.: 66170 Cov.: 32

Gnomad AFR AF: 0.803

Gnomad AMI AF: 0.843

Gnomad AMR AF: 0.958

Gnomad ASJ AF: 0.994

Gnomad EAS AF: 0.874

Gnomad SAS AF: 0.952

Gnomad FIN AF: 0.980

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.991

Gnomad OTH AF: 0.936

GnomAD4 exome AF: 0.977 AC: 986749 AN: 1009812 Hom.: 482920 Cov.: 13 AF XY: 0.978 AC XY: 504185 AN XY: 515790

African (AFR) AF: 0.794 AC: 19131 AN: 24100

American (AMR) AF: 0.943 AC: 33347 AN: 35374

Ashkenazi Jewish (ASJ) AF: 0.993 AC: 22096 AN: 22260

East Asian (EAS) AF: 0.869 AC: 30246 AN: 34806

South Asian (SAS) AF: 0.958 AC: 67082 AN: 70006

European-Finnish (FIN) AF: 0.977 AC: 35389 AN: 36208

Middle Eastern (MID) AF: 0.982 AC: 3628 AN: 3694

European-Non Finnish (NFE) AF: 0.992 AC: 732059 AN: 738044

Other (OTH) AF: 0.966 AC: 43771 AN: 45320

GnomAD4 genome AF: 0.929 AC: 141402 AN: 152248 Hom.: 66197 Cov.: 32 AF XY: 0.930 AC XY: 69189 AN XY: 74436

African (AFR) AF: 0.802 AC: 33304 AN: 41506

American (AMR) AF: 0.958 AC: 14653 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.994 AC: 3451 AN: 3472

East Asian (EAS) AF: 0.874 AC: 4523 AN: 5178

South Asian (SAS) AF: 0.951 AC: 4588 AN: 4822

European-Finnish (FIN) AF: 0.980 AC: 10408 AN: 10618

Middle Eastern (MID) AF: 0.976 AC: 287 AN: 294

European-Non Finnish (NFE) AF: 0.991 AC: 67440 AN: 68040

Other (OTH) AF: 0.937 AC: 1979 AN: 2112

Alfa AF: 0.969 Hom.: 87921

Bravo AF: 0.918

Asia WGS AF: 0.903 AC: 3137 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.42
DANN	Benign	0.55
PhyloP100		-0.47
Mutation Taster		=100/0	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: rs3816781; hg19: chr2-179639297;