2-88027888-C-G

Variant names:

• chr2-88027888-C-G
• rs767205744
• NM_016618.3:c.676G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016618.3(KRCC1):​c.676G>C​(p.Val226Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V226I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KRCC1 NM_016618.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.236
• Publications: 0 publications found

Genes affected

KRCC1 (HGNC:28039): (lysine rich coiled-coil 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.035152525).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016618.3. 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
	KRCC1	NM_016618.3	MANE Select	c.676G>C	p.Val226Leu	missense	Exon 4 of 4	NP_057702.1	Q9NPI7
	KRCC1	NM_001304526.2		c.676G>C	p.Val226Leu	missense	Exon 4 of 4	NP_001291455.1	Q9NPI7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRCC1	ENST00000347055.4	TSL:1 MANE Select	c.676G>C	p.Val226Leu	missense	Exon 4 of 4	ENSP00000340083.3	Q9NPI7
	KRCC1	ENST00000672766.1		c.676G>C	p.Val226Leu	missense	Exon 2 of 2	ENSP00000499834.1	Q9NPI7
	KRCC1	ENST00000910792.1		c.676G>C	p.Val226Leu	missense	Exon 4 of 4	ENSP00000580851.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461766 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727172

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

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.87
DEOGEN2	Benign	0.0052	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.24
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.0040
Sift	Benign	0.10	T
Sift4G	Benign	0.25	T
Polyphen		0.022	B
Vest4		0.086
MutPred		0.10		Loss of methylation at K228 (P = 0.0752)
MVP		0.15
MPC		0.17
ClinPred		0.088	T
GERP RS		0.59
Varity_R		0.044
gMVP		0.0095
Mutation Taster		=94/6	polymorphism

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: rs767205744; hg19: chr2-88327407;