NM_001267550.2:c.39709+6C>T

Variant names:

• chr2-178650745-G-A
• rs72650067
• NM_001267550.2:c.39709+6C>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.39709+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00704 in 1,598,416 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (47 hom.)
• Consequence: TTN NM_001267550.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002156
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: -1.14
• 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 (BayesDel_noAF=-0.89).
• BP6: Variant 2-178650745-G-A is Benign according to our data. Variant chr2-178650745-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46930.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 = 0.00518 (789/152264) while in subpopulation NFE AF = 0.00846 (575/68000). AF 95% confidence interval is 0.00788. There are 4 homozygotes in GnomAd4. There are 368 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.39709+6C>T		splice_region intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.35188+6C>T		splice_region intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.32407+6C>T		splice_region 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.39709+6C>T		splice_region intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.39709+6C>T		splice_region intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.39433+6C>T		splice_region intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00519 AC: 789 AN: 152146 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00845

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00535 AC: 1215 AN: 227250 AF XY: 0.00515

Gnomad AFR exome AF: 0.00116

Gnomad AMR exome AF: 0.00169

Gnomad ASJ exome AF: 0.00955

Gnomad EAS exome AF: 0.000301

Gnomad FIN exome AF: 0.00551

Gnomad NFE exome AF: 0.00842

Gnomad OTH exome AF: 0.00622

GnomAD4 exome AF: 0.00723 AC: 10461 AN: 1446152 Hom.: 47 Cov.: 31 AF XY: 0.00720 AC XY: 5167 AN XY: 717718

African (AFR) AF: 0.00109 AC: 36 AN: 33178

American (AMR) AF: 0.00184 AC: 79 AN: 43046

Ashkenazi Jewish (ASJ) AF: 0.0100 AC: 258 AN: 25738

East Asian (EAS) AF: 0.000153 AC: 6 AN: 39090

South Asian (SAS) AF: 0.00214 AC: 178 AN: 83244

European-Finnish (FIN) AF: 0.00534 AC: 281 AN: 52614

Middle Eastern (MID) AF: 0.00435 AC: 25 AN: 5744

European-Non Finnish (NFE) AF: 0.00840 AC: 9266 AN: 1103710

Other (OTH) AF: 0.00555 AC: 332 AN: 59788

GnomAD4 genome AF: 0.00518 AC: 789 AN: 152264 Hom.: 4 Cov.: 32 AF XY: 0.00494 AC XY: 368 AN XY: 74438

African (AFR) AF: 0.00154 AC: 64 AN: 41580

American (AMR) AF: 0.00216 AC: 33 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5168

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4826

European-Finnish (FIN) AF: 0.00405 AC: 43 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00846 AC: 575 AN: 68000

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00855 Hom.: 2

Bravo AF: 0.00499

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	5	not provided (5)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.39
DANN	Benign	0.84
PhyloP100		-1.1
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.080		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: rs72650067; hg19: chr2-179515472;