rs147212187

Variant names:

• chr12-49051745-G-C
• rs147212187
• NM_003482.4:c.1938C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-49051745-G-C
• chr12-49051745-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003482.4(KMT2D):​c.1938C>G​(p.Pro646Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000985 in 136,058 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00098 (3 hom., cov: 28)
  • Exomes 𝑓: 0.0010 (30 hom.)
  • Failed GnomAD Quality Control
• Consequence: KMT2D NM_003482.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.00

Genes affected

KMT2D (HGNC:7133): (lysine methyltransferase 2D) The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complex called ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to be a cause of Kabuki syndrome. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-49051745-G-C is Benign according to our data. Variant chr12-49051745-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 158747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000985 (134/136058) while in subpopulation EAS AF= 0.0247 (110/4446). AF 95% confidence interval is 0.021. There are 3 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 134 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.1938C>G	p.Pro646Pro	synonymous_variant	Exon 11 of 55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.1938C>G	p.Pro646Pro	synonymous_variant	Exon 11 of 55	5	NM_003482.4	ENSP00000301067.7
KMT2D	ENST00000683543.2	c.1938C>G	p.Pro646Pro	synonymous_variant	Exon 11 of 56			ENSP00000506726.1
KMT2D	ENST00000685166.1	c.1938C>G	p.Pro646Pro	synonymous_variant	Exon 10 of 54			ENSP00000509386.1
KMT2D	ENST00000692637.1	c.1938C>G	p.Pro646Pro	synonymous_variant	Exon 10 of 54			ENSP00000509666.1

Frequencies

GnomAD3 genomes AF: 0.000993 AC: 135 AN: 135952 Hom.: 3 Cov.: 28

Gnomad AFR AF: 0.000334

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0249

Gnomad SAS AF: 0.00144

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000793

Gnomad OTH AF: 0.000537

GnomAD3 exomes AF: 0.00186 AC: 457 AN: 246138 Hom.: 9 AF XY: 0.00168 AC XY: 224 AN XY: 133462

Gnomad AFR exome AF: 0.000260

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0236

Gnomad SAS exome AF: 0.000362

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000808

Gnomad OTH exome AF: 0.000838

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000998 AC: 1410 AN: 1413366 Hom.: 30 Cov.: 35 AF XY: 0.000938 AC XY: 660 AN XY: 703816

Gnomad4 AFR exome AF: 0.000123

Gnomad4 AMR exome AF: 0.0000904

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0318

Gnomad4 SAS exome AF: 0.000258

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000392

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.000985 AC: 134 AN: 136058 Hom.: 3 Cov.: 28 AF XY: 0.000952 AC XY: 63 AN XY: 66168

Gnomad4 AFR AF: 0.000333

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0247

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000793

Gnomad4 OTH AF: 0.000532

Alfa AF: 0.000222 Hom.: 0

Bravo AF: 0.000926

EpiCase AF: 0.0000547

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jun 26, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 11, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kabuki syndrome 1 Benign:1

Aug 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kabuki syndrome Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.1
DANN	Benign	0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs147212187; hg19: chr12-49445528;