rs61233923

Variant names:

• chr2-178747148-A-G
• rs61233923
• NM_001267550.2:c.11312-5227T>C

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.11312-5227T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 1,574,636 control chromosomes in the GnomAD database, including 421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (301 hom., cov: 31)
  • Exomes 𝑓: 0.0018 (120 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.41
• 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-178747148-A-G is Benign according to our data. Variant chr2-178747148-A-G is described in ClinVar as Benign. ClinVar VariationId is 47781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.11312-5227T>C		intron	N/A	NP_001254479.2
	TTN	NM_133379.5		c.15252T>C	p.Tyr5084Tyr	synonymous	Exon 46 of 46	NP_596870.2
	TTN	NM_001256850.1		c.10361-5227T>C		intron	N/A	NP_001243779.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.11312-5227T>C		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.11312-5227T>C		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.11036-5227T>C		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0361 AC: 4462 AN: 123540 Hom.: 302 Cov.: 31

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.000336

Gnomad EAS AF: 0.000731

Gnomad SAS AF: 0.00188

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.0208

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.0352

GnomAD2 exomes AF: 0.00411 AC: 1012 AN: 246238 AF XY: 0.00292

Gnomad AFR exome AF: 0.0609

Gnomad AMR exome AF: 0.00218

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000152

Gnomad OTH exome AF: 0.00251

GnomAD4 exome AF: 0.00183 AC: 2662 AN: 1450992 Hom.: 120 Cov.: 34 AF XY: 0.00159 AC XY: 1145 AN XY: 722054

African (AFR) AF: 0.0708 AC: 2089 AN: 29506

American (AMR) AF: 0.00358 AC: 158 AN: 44148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25892

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.000245 AC: 21 AN: 85834

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53160

Middle Eastern (MID) AF: 0.00275 AC: 15 AN: 5448

European-Non Finnish (NFE) AF: 0.0000578 AC: 64 AN: 1107780

Other (OTH) AF: 0.00526 AC: 314 AN: 59656

GnomAD4 genome AF: 0.0363 AC: 4484 AN: 123644 Hom.: 301 Cov.: 31 AF XY: 0.0345 AC XY: 2075 AN XY: 60078

African (AFR) AF: 0.130 AC: 4197 AN: 32328

American (AMR) AF: 0.0108 AC: 137 AN: 12712

Ashkenazi Jewish (ASJ) AF: 0.000336 AC: 1 AN: 2978

East Asian (EAS) AF: 0.000733 AC: 3 AN: 4092

South Asian (SAS) AF: 0.00216 AC: 8 AN: 3708

European-Finnish (FIN) AF: 0.000753 AC: 6 AN: 7966

Middle Eastern (MID) AF: 0.0220 AC: 4 AN: 182

European-Non Finnish (NFE) AF: 0.00115 AC: 66 AN: 57224

Other (OTH) AF: 0.0349 AC: 62 AN: 1774

Alfa AF: 0.0235 Hom.: 71

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.0040
DANN	Benign	0.55
PhyloP100		-1.4
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: rs61233923; hg19: chr2-179611875; COSMIC: COSV60262679; COSMIC: COSV60262679;