rs200819643

Variant names:

• chr2-178653325-A-G
• rs200819643
• NM_001267550.2:c.38708-4T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178653325-A-G
• chr2-178653325-A-C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_001267550.2(TTN):​c.38708-4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 148,882 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0026 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0031 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 splice_region, intron
• Scores: Splicing: ADA: 0.0001705
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -3.93
• 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-178653325-A-G is Benign according to our data. Variant chr2-178653325-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.38708-4T>C		splice_region intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34523-784T>C		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31742-784T>C		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.38708-4T>C		splice_region intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.38708-4T>C		splice_region intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.38432-4T>C		splice_region intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 393 AN: 148766 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000533

Gnomad AMI AF: 0.00112

Gnomad AMR AF: 0.00175

Gnomad ASJ AF: 0.00147

Gnomad EAS AF: 0.00379

Gnomad SAS AF: 0.00757

Gnomad FIN AF: 0.00394

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.00361

Gnomad OTH AF: 0.00245

GnomAD2 exomes AF: 0.00566 AC: 1365 AN: 241194 AF XY: 0.00608

Gnomad AFR exome AF: 0.000409

Gnomad AMR exome AF: 0.00478

Gnomad ASJ exome AF: 0.00526

Gnomad EAS exome AF: 0.00514

Gnomad FIN exome AF: 0.00626

Gnomad NFE exome AF: 0.00467

Gnomad OTH exome AF: 0.00595

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00310 AC: 4427 AN: 1427846 Hom.: 5 Cov.: 34 AF XY: 0.00315 AC XY: 2235 AN XY: 710422

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

African (AFR) AF: 0.000391 AC: 13 AN: 33284

American (AMR) AF: 0.00339 AC: 148 AN: 43616

Ashkenazi Jewish (ASJ) AF: 0.00175 AC: 45 AN: 25772

East Asian (EAS) AF: 0.00175 AC: 65 AN: 37210

South Asian (SAS) AF: 0.00586 AC: 493 AN: 84184

European-Finnish (FIN) AF: 0.00406 AC: 208 AN: 51200

Middle Eastern (MID) AF: 0.00263 AC: 13 AN: 4934

European-Non Finnish (NFE) AF: 0.00304 AC: 3312 AN: 1088734

Other (OTH) AF: 0.00221 AC: 130 AN: 58912

⚠️ 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: 0.00264 AC: 393 AN: 148882 Hom.: 0 Cov.: 29 AF XY: 0.00277 AC XY: 201 AN XY: 72674

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

African (AFR) AF: 0.000532 AC: 22 AN: 41386

American (AMR) AF: 0.00175 AC: 26 AN: 14868

Ashkenazi Jewish (ASJ) AF: 0.00147 AC: 5 AN: 3400

East Asian (EAS) AF: 0.00381 AC: 18 AN: 4730

South Asian (SAS) AF: 0.00758 AC: 35 AN: 4618

European-Finnish (FIN) AF: 0.00394 AC: 40 AN: 10144

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.00361 AC: 240 AN: 66492

Other (OTH) AF: 0.00242 AC: 5 AN: 2062

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00578 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	2.2
DANN	Benign	0.86
PhyloP100		-3.9
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.10		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: rs200819643; hg19: chr2-179518052; COSMIC: COSV60438953; COSMIC: COSV60438953;