NM_003737.4:c.1902C>T

Variant names:

• chr11-6634202-G-A
• rs997263
• NM_003737.4:c.1902C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003737.4(DCHS1):​c.1902C>T​(p.His634His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 1,613,462 control chromosomes in the GnomAD database, including 112,556 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9698 hom., cov: 33)
  • Exomes 𝑓: 0.37 (102858 hom.)
• Consequence: DCHS1 NM_003737.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.559
• Publications: 22 publications found

Genes affected

DCHS1 (HGNC:13681): (dachsous cadherin-related 1) This gene is a member of the cadherin superfamily whose members encode calcium-dependent cell-cell adhesion molecules. The encoded protein has a signal peptide, 27 cadherin repeat domains and a unique cytoplasmic region. This particular cadherin family member is expressed in fibroblasts but not in melanocytes or keratinocytes. The cell-cell adhesion of fibroblasts is thought to be necessary for wound healing. [provided by RefSeq, Jul 2008]

DCHS1 Gene-Disease associations (from GenCC):

• mitral valve prolapse, myxomatous 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• van Maldergem syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• van Maldergem syndrome

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• familial mitral valve prolapse

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000255410 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 11-6634202-G-A is Benign according to our data. Variant chr11-6634202-G-A is described in ClinVar as Benign. ClinVar VariationId is 259136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.559 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003737.4. 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
	DCHS1	NM_003737.4	MANE Select	c.1902C>T	p.His634His	synonymous	Exon 3 of 21	NP_003728.1	Q96JQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCHS1	ENST00000299441.5	TSL:1 MANE Select	c.1902C>T	p.His634His	synonymous	Exon 3 of 21	ENSP00000299441.3	Q96JQ0
	ENSG00000255410	ENST00000526633.1	TSL:3	n.211-730G>A		intron	N/A
	ENSG00000255410	ENST00000656961.1		n.309+2773G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53661 AN: 151964 Hom.: 9694 Cov.: 33

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.367

GnomAD2 exomes AF: 0.373 AC: 93582 AN: 250790 AF XY: 0.373

Gnomad AFR exome AF: 0.276

Gnomad AMR exome AF: 0.352

Gnomad ASJ exome AF: 0.411

Gnomad EAS exome AF: 0.447

Gnomad FIN exome AF: 0.393

Gnomad NFE exome AF: 0.385

Gnomad OTH exome AF: 0.390

GnomAD4 exome AF: 0.374 AC: 546697 AN: 1461378 Hom.: 102858 Cov.: 58 AF XY: 0.374 AC XY: 271614 AN XY: 726958

African (AFR) AF: 0.277 AC: 9256 AN: 33474

American (AMR) AF: 0.352 AC: 15734 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 10670 AN: 26120

East Asian (EAS) AF: 0.461 AC: 18288 AN: 39694

South Asian (SAS) AF: 0.328 AC: 28240 AN: 86194

European-Finnish (FIN) AF: 0.388 AC: 20689 AN: 53384

Middle Eastern (MID) AF: 0.394 AC: 2269 AN: 5766

European-Non Finnish (NFE) AF: 0.377 AC: 419249 AN: 1111692

Other (OTH) AF: 0.369 AC: 22302 AN: 60364

GnomAD4 genome AF: 0.353 AC: 53695 AN: 152084 Hom.: 9698 Cov.: 33 AF XY: 0.353 AC XY: 26231 AN XY: 74334

African (AFR) AF: 0.280 AC: 11606 AN: 41482

American (AMR) AF: 0.367 AC: 5615 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1441 AN: 3466

East Asian (EAS) AF: 0.447 AC: 2310 AN: 5164

South Asian (SAS) AF: 0.339 AC: 1634 AN: 4814

European-Finnish (FIN) AF: 0.384 AC: 4063 AN: 10584

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.380 AC: 25827 AN: 67968

Other (OTH) AF: 0.365 AC: 770 AN: 2110

Alfa AF: 0.369 Hom.: 7182

Bravo AF: 0.347

Asia WGS AF: 0.363 AC: 1267 AN: 3478

EpiCase AF: 0.373

EpiControl AF: 0.375

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.5
DANN	Benign	0.85
PhyloP100		0.56
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: rs997263; hg19: chr11-6655433; COSMIC: COSV55037241;